Drug Interactions

DRUG INTERACTIONS

Clin Pharmacokinet 1999 Jun; 36 (6): 425-438 0312-5963/99/0006-0425/$07.00/0 © Adis International Limited. All rights reserved.

Drug Interactions with Tobacco Smoking
An Update
Shoshana Zevin1 and Neal L. Benowitz2
1 Department of Internal Medicine, Shaare Zedek Medical Center, Jerusalem, Israel 2 Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospital Medical Center and the Department of Medicine and Psychiatry, University of California, San Francisco, California, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Polycyclic Aromatic Hydrocarbons . . . . . . . . . . . . . . 1.1 Cytochrome P450 (CYP) 1A1 . . . . . . . . . . . . . . . 1.2 CYP1A2 . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3 CYP2E1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4 Uridine 5′-Diphosphate (UDP)-Glucuronosyltransferases 2. Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Carbon Monoxide . . . . . . . . . . . . . . . . . . . . . . . . 4. Heavy Metals . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Smoking and Drug Interactions . . . . . . . . . . . . . . . . . 5.1 Theophylline . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Caffeine . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Tacrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4 Paracetamol (Acetaminophen) . . . . . . . . . . . . . 5.5 Psychoactive Drugs . . . . . . . . . . . . . . . . . . . . 5.5.1 Antidepressants . . . . . . . . . . . . . . . . . . . 5.5.2 Benzodiazepines . . . . . . . . . . . . . . . . . . 5.5.3 Antipsychotics . . . . . . . . . . . . . . . . . . . . 5.6 Cardiovascular Drugs . . . . . . . . . . . . . . . . . . . 5.6.1 β-Blockers . . . . . . . . . . . . . . . . . . . . . . . 5.6.2 Antiarrhythmics . . . . . . . . . . . . . . . . . . . 5.7 Anticoagulants . . . . . . . . . . . . . . . . . . . . . . . 5.7.1 Warfarin . . . . . . . . . . . . . . . . . . . . . . . 5.7.2 Heparin . . . . . . . . . . . . . . . . . . . . . . . . 5.8 Steroid Hormones . . . . . . . . . . . . . . . . . . . . . . 5.9 Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.10 Alcohol (Ethanol) . . . . . . . . . . . . . . . . . . . . . . 5.11 Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.11.1 Dextropropoxyphene . . . . . . . . . . . . . . . . 5.11.2 Pentazocine . . . . . . . . . . . . . . . . . . . . . 5.11.3 Codeine . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426 427 427 428 428 429 429 429 431 431 431 431 432 432 432 432 432 432 433 433 433 433 433 433 433 434 434 434 434 434 434 434

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Abstract

Cigarette smoking remains highly prevalent in most countries. It can affect drug therapy by both pharmacokinetic and pharmacodynamic mechanisms. Enzymes induced by tobacco smoking may also increase the risk of cancer by enhancing the metabolic activation of carcinogens. Polycyclic aromatic hydrocarbons in tobacco smoke are believed to be responsible for the induction of cytochrome P450 (CYP) 1A1, CYP1A2 and possibly CYP2E1. CYP1A1 is primarily an extrahepatic enzyme found in lung and placenta. There are genetic polymorphisms in the inducibility of CYP1A1, with some evidence that high inducibility is more common in patients with lung cancer. CYP1A2 is a hepatic enzyme responsible for the metabolism of a number of drugs and activation of some procarcinogens. Caffeine demethylation, using blood clearance or urine metabolite data, has been used as an in vivo marker of CYP1A2 activity, clearly demonstrating an effect of cigarette smoking. CYP2E1 metabolises a number of drugs as well as activating some carcinogens. Our laboratory has found in an intraindividual study that cigarette smoking significantly enhances CYP2E1 activity as measured by the clearance of chlorzoxazone. In animal studies, nicotine induces the activity of several enzymes, including CYP2E1, CYP2A1/2A2 and CYP2B1/2B2, in the brain, but whether this effect is clinically significant is unknown. Similarly, although inhibitory effects of the smoke constituents carbon monoxide and cadmium on CYP enzymes have been observed in vitro and in animal studies, the relevance of this inhibition to humans has not yet been established. The mechanism involved in most interactions between cigarette smoking and drugs involves the induction of metabolism. Drugs for which induced metabolism because of cigarette smoking may have clinical consequence include theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide and estradiol. Cigarette smoking results in faster clearance of heparin, possibly related to smoking-related activation of thrombosis with enhanced heparin binding to antithrombin III. Cutaneous vasoconstriction by nicotine may slow the rate of insulin absorption after subcutaneous administration. Pharmacodynamic interactions have also been described. Cigarette smoking is associated with a lesser magnitude of blood pressure and heart rate lowering during treatment with β-blockers, less sedation from benzodiazepines and less analgesia from some opioids, most likely reflecting the effects of the stimulant actions of nicotine. The impact of cigarette smoking needs to be considered in planning and assessing responses to drug therapy. Cigarette smoking should be specifically studied in clinical trials of new drugs.

Tobacco smoking is still a major health concern, with about 25% of the US population smoking tobacco products. Smoking is the cause of much morbidity and mortality. Among their various biological effects, cigarette smoke constituents induce several drug-metabolising enzymes. Enzyme induction has implications for medication use since, as a result of interaction with cigarette smoke, drug clearance (and thus dose re© Adis International Limited. All rights reserved.

quirements) may change. Many chemical carcinogens are activated by various cytochrome P450 (CYP) enzymes to active carcinogens. Induction of these enzymes by cigarette smoke may be important for cancer development. Cigarette smoke is composed of volatile and particulate phases. The gaseous portion comprises about 95% of cigarette smoke by weight. Some 500 gaseous compounds, including nitrogen, carbon
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monoxide, carbon dioxide, ammonia, hydrogen cyanide and benzene, have been identified in the volatile phase. The other 5% of cigarette smoke is composed of particulates. There are about 3500 different compounds in the particulate phase, of which the major one is the alkaloid nicotine. Other alkaloids include nornicotine, anatabine and anabasine. The particulate matter minus its alkaloid and water content is called tar. Many carcinogens, among them polynuclear aromatic hydrocarbons, N-nitrosamines and aromatic amines, have been identified in cigarette tar.[1,2] Polycyclic aromatic hydrocarbons, a product of incomplete combustion of organic matter (tobacco in the instance of cigarette smoke), are primarily responsible for inducing drug-metabolising enzymes and, in turn, are converted by the induced enzymes to active carcinogens.[3,4] Other substances in cigarette smoke which may interact with metabolising enzymes are acetone, pyridine, benzene, nicotine, carbon monoxide and heavy metals (e.g. cadmium). In this paper we will review the literature on the effect of cigarette smoke constituents on drugmetabolising enzymes, the molecular basis for such effects and the clinically important ways in which cigarette smoking affects drug action, including both pharmacokinetic and pharmacodynamic interactions. 1. Polycyclic Aromatic Hydrocarbons
1.1 Cytochrome P450 (CYP) 1A1

CYP1A1 is an enzyme involved in the activation of procarcinogens.[5-8] This isoform is mainly extrahepatic in humans and is found in the lung and placenta.[9] CYP1A1 can be induced by aryl hydrocarbons (Ah), including benzo[a]pyrene, benzofluorene, tetrachlorodibenzo-p-dioxin (TCDD) and fluoranthene, all of which are abundant in cigarette smoke. CYP1A1 also activates benzo[a]pyrene, which is a major carcinogen in cigarette smoke, resulting in the appearance of DNA adducts.[10-12] There is a strong association between a high level of activity of CYP1A1 and the risk of lung cancer.[13,14]
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The activity of CYP1A1 can be assessed in vitro in lymphocytes or bronchoepithelial cells by using ethoxyresorufin as a substrate and measuring the activity of ethoxyresorufin O-deethylase (EROD).[15] Recently, the expression of CYP1A1 has been measured in bronchoepithelial cells by reverse transcriptase–polymerase chain reaction (RT-PCR). [16] Protein levels of CYP1A1 can also be determined by specific antibodies.[17] The mechanism of CYP1A1 induction by Ah has been extensively studied and involves mainly transcriptional events. Binding of Ah to the Ah receptor results in the dissociation of the Hsp90 protein from the Ah receptor, and binding of the Ah-Ah receptor complex with the Ah receptor nuclear translocator (ARNT).[18,19] This heterodimer then binds to specific DNA sequences called Ah-responsive elements (AhRE) on the CYP1A1 gene,[20,21] leading to transcriptional activation of the CYP1A1 gene and enhanced expression.[22] There is genetic polymorphism in the inducibility of CYP1A1 by polycyclic aromatic hydrocarbons, with a high inducibility phenotype being more common in patients with lung cancer.[14,23] Willey et al.[16] found CYP1A1 significantly expressed in bronchoepithelial cells of smokers, but undetectable in nonsmokers, with significant interindividual variability in the expression; this was not found for some of the other enzymes studied. Another study found that in a Caucasian population 21% had a high CYP1A1 induction phenotype and 89% a low induction phenotype.[15] The possible location of the polymorphisms could reside within the genes for CYP1A1 itself, the Ah receptor or the ARNT.[24] A mutation in the 3′-flanking region of the CYP1A1 gene generates an MspI restriction fragment length polymorphism (RFLP) which has been genetically linked to a point mutation in the coding region that results in the substitution of Ile for Val in the haem-binding region. The m1 allele with Ile has low functional activity and the rarer m2 allele with Val has high activity. However, no consistent correlation was found between m1/m2 heterozygosity or m2/m2 homozygosity and develClin Pharmacokinet 1999 Jun; 36 (6)

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opment of lung cancer.[5,25-29] Another polymorphism, coupled to the m2 allele, is substitution of Val for Ile in codon 462 in exon 7 in the CYP1A1 gene, conferring high CYP1A1 activity.[30,31] The combination of either the rare m2 allele or the Ile462→Val substitution with a deficient Mu gene of glutathione transferase (GSTM1) was found to be associated with an increased risk of squamous cell carcinoma of the lung and esophageal carcinoma.[29,32,33] Although the exact sites of CYP1A1 inducibility polymorphisms have not yet been identified, it is likely that these polymorphisms explain in part different susceptibility to lung cancer among smokers. The dose-effect relationship between the induction of CYP1A1 and the cumulative number of cigarettes smoked is not clear. There are data indicating that aryl hydrocarbon hydroxylase (AHH) activity positively correlates with the number of cigarettes smoked per day, and the odds ratio for lung cancer increases with the number of cigarettes smoked.[13,34] However, it is at lower levels of exposure (less than 30 packs/year) that genetic polymorphism of CYP1A1 inducibility confer an increased risk of developing lung cancer: about a 2-fold increase in the odds ratio for developing lung cancer was reported for individuals with MspI or exon 7 polymorphisms.[29,34,35]
1.2 CYP1A2

identified in the 5′-flanking region of the CYP1A2 gene as participating in enzyme activation. X1 binds to the Ah receptor complex and is necessary for the full activation of transcription. However, deletion of X1 does not abolish the induction but decreases it by about 50%.[37,39] Caffeine demethylation with quantitation of the ratio of urinary concentrations of 3′-demethylation products in vivo, and phenacetin O-deethylation in vitro, have been used as markers for CYP1A2 activity.[40-42] CYP1A2 protein levels can be assessed by specific antibodies[17] and CYP1A2 mRNA can be assessed by RT-PCR.[43] There is considerable individual variation in CYP1A2 activity and content.[37,43] Utilising different methods for assessing CYP1A2 activity, some investigators found a bimodal or trimodal distribution,[40,44,45] whereas others found a log-normal distribution of enzyme activity.[41] However, a specific site of genetic polymorphism of CYP1A2 has not yet been identified.[43,44] Also, there may be differences between types of tobacco – in one study, smokers of blonde tobacco demonstrated induction of CYP1A2 activity, whereas smokers of black tobacco did not.[40]
1.3 CYP2E1

CYP1A2 is responsible for metabolism of several drugs, including caffeine (by N-demethylation), theophylline, paracetamol (acetaminophen) and tacrine,[36] as well as for N-oxidation of some procarcinogenic arylamines, heterocyclic amines and nitrosamines, and aflatoxin B1.[37] This is primarily a hepatic enzyme.[9] Polycyclic aromatic hydrocarbons found in cigarette smoke are known inducers of this system. The mechanisms of induction are less well characterised than for CYP1A1, but seem to involve transcriptional events. It is probable that CYP1A2 activation is tissue-specific. 3-Methylcholanthrene-induced enzyme activation was detected in hepatoma but not in breast cancer cell lines.[38] Two distinct DNA sequences (X1 and X2) were
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CYP2E1 is involved in conversion of small organic compounds, such as carbon tetrachloride, Nnitrosodimethylamine (NDMA), paracetamol and alcohol (ethanol), into reactive intermediate metabolites.[9] Some of the substrates for CYP2E1 are found in tobacco smoke (i.e. NDMA, pyridine, benzene, acetone, styrene and vinyl chloride). Many of these are procarcinogens that are activated by CYP2E1.[46] Chlorzoxasone clearance is used as an in vivo marker for CYP2E1 activity. CYP2E1 is induced by alcohol.[47,48] There are gender differences in CYP2E1 activity, with women having lower enzyme activity compared with men.[48,49] The mechanisms of induction probably involve both transcriptional activation and post-transcriptional stabilisation.[27] The association between smoking-related cancers and CYP2E1 activity has not been well established to date, unlike for CYP1A1. Several RFLPs of the
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CYP2E1 gene have been described in association with lung cancer.[27,50] However, all the polymorphisms reported so far have been found in noncoding regions of the CYP2E1 gene and their significance in relation to lung cancer is uncertain.[27,28] It has been demonstrated that tobacco smoke significantly enhances CYP2E1 expression in mouse lung[51] and CYP2E1 metabolic activity in liver.[52] Seree et al.[53] demonstrated high inducibility of CYP2E1 by tobacco smoke in mouse kidney, both as expression by RT-PCR and activity by NDMA demethylase. Some studies in humans have failed to demonstrate significant inducibility of CYP2E1 in smokers. Girre et al.[47] found no difference in CYP2E1 activity, as assessed by chlorzoxazone clearance, between male non-alcoholic smokers and nonsmokers. Interestingly, chlorzoxazone metabolism was enhanced in non-alcoholic female smokers,[48] but not in alcoholic smokers. In our laboratory, we found in a intraindividual crossover study (i.e., comparing smoking with no smoking conditions) that cigarette smoking enhanced chlorzoxazone metabolism in males, but the effect was modest (24% increase in clearance).[54]
1.4 Uridine 5′-Diphosphate (UDP)-Glucuronosyltransferases

ers.[61] We have recently found that smoking markedly accelerates the O-glucuronidation of trans-3′hydroxycotinine (a metabolite of nicotine), but has no effect on the N-glucuronidation of nicotine or cotinine (unpublished data). 2. Nicotine Nicotine is the major alkaloid in tobacco smoke and is mainly metabolised in the liver by CYP2A6. Cotinine is its major metabolite. It has been proposed that nicotine induces its own clearance; however, smokers have a lower clearance of nicotine compared with nonsmokers.[62] Cotinine administration was found to have no effect on either nicotine or cotinine clearance or drug half-life (t1⁄2).[63] Nicotine induces several CYP isoforms in rat brain. In one study, nicotine administration twice daily for 10 days at doses similar to the nicotine content of a cigarette resulted in elevated levels of CYP2B1/2B2 in rat brains, as well as enhanced activity of these enzymes as evidenced by benzyloxyresorufin and pentoxyresorufin activity.[64] No effect was found on either CYP2B1/2B2 content or activity in the livers of the same animals. In another study, Anadatheerthavarada et al.[65] found that nicotine increased both content and activity of CYP2E1 in rat brain, but not in the liver. The induction was found in all the brain regions studied. Nicotine also induced CYP2A1/2A2 in rat brain; however, this induction was apparent only in brain stem and hippocampus, while in cortex, thalamus, and striatum nicotine decreased CYP2A1/ 2A2 content and activity. It is possible that the differential effects of nicotine on CYP enzymes in different brain areas play a role in a complex doseeffect relationship of nicotine. 3. Carbon Monoxide Carbon monoxide (CO) is a well known in vitro inhibitor of CYP enzymes. The effect of CO on the CYP system has been mainly studied in animal tissues and in perfused organs. There is a doseeffect response: the higher the CO concentration, the more pronounced the inhibition.[66-68] The inhibition seems to be a direct effect of CO on the
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There are 2 families of uridine 5′-diphosphate (UDP)-glucuronosyltransferases with overlapping substrate selectivity.[55] Some of these enzymes are induced by components of cigarette smoke, notably by polycyclic aryl hydrocarbons (i.e. 3-methylcholanthrene).[56] In mice, cigarette smoke exposure increased the glucuronidation of several phenolic chemicals in microsomes from liver and lung.[52] Cigarette smoke exerts differential effects on UDP-glucuronosyltransferases; in human liver microsomes the glucuronidation of 1-naphthol was increased, whereas there was no change in the glucuronidation of morphine or bilirubin.[57] Increased glucuronidation of mexiletine, propranolol and codeine was also found in smokers.[58-60] The oral clearance of oxazepam, which is metabolised by glucuronide conjugation, is reported to be faster in smokers compared with nonsmok© Adis International Limited. All rights reserved.

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Table I. Pharmacokinetic interactions between smoking and drugs Drug Alcohol (ethanol) Benzodiazepines (diazepam, lorazepam, midazolam, chlordiazepoxide) Bupropion Caffeine Chlorpromazine Clorazepate Clozapine Codeine Estradiol Ethinyl estradiol (levonorgestrel) Flecainide Fluvoxamine Glucocorticoids (prednisone, prednisolone, dexamethasone) Haloperidol Heparin Imipramine Insulin Lidocaine Mexiletine Nortriptyline Olanzapine Paracetamol (acetaminophen) Propranolol Quinidine Tacrine Theophylline Warfarin Interaction Yes - delayed gastric emptying No Effects Decreased rate of absorption and peak serum concentrations

No Yes induction of CYP1A2 Yes Yes Yes - induction of CYP1A2 Yes - increased glucuronidation Yes - increased 2-hydroxylation No Yes Yes - induction of CYP1A2 No Yes Yes - mechanism unclear Yes Yes - decreased subcutaneous absorption Yes - decreased oral bioavailability Yes – increased oxidation and glucuronidation Unclear Yes - induction of CYP1A2 No Yes - increased side-chain oxidation and glucuronidation No Yes - induction of CYP1A2 Yes - induction of CYP1A2 Yes Increased clearance: decreased AUC (10-fold); decreased mean plasma concentrations (3-fold); decreased t1⁄2 (by 50%) Increased metabolic clearance (by 58 to 100%); decreased t1⁄2 (by 63%) and increased Vd (by 31%) Increased clearance (by 13%); decreased plasma concentrations (by 13%). No effect on prothrombin time Increased oral clearance (by 77%) Increased clearance (by 44%) and decreased serum concentrations (by 70%). Clinical significance unclear Increased clearance. Decreased t1⁄2 Decreased serum concentrations. No clinical effect Possibly higher insulin requirements in smokers Decreased AUC (by 200%) Increased oral clearance (25%); decreased t1⁄2 (36%) No clinical effect Increased clearance (by 98%) Increased clearance (by 61%); decreased trough serum concentrations (by 25%); increased dose requirements (by 17%) Increased metabolic clearance; decreased AUC (by 44%); decreased plasma concentrations (by 47%) Increased clearance (by 56%) Decrease in AUC (by 36%) and serum concentrations (by 24%). Clinical significance unclear Decreased AUC, decreased t1⁄2 of N-desmethyldiazepam Increased clearance; decreased plasma concentrations (by 28%) No overall effect on AUC, t1⁄2 and serum concentrations Possibly anti-estrogenic effects

AUC = area under the concentration-time curve; t1⁄2 = half-life; Vd = volume of distribution.

metabolising enzymes, rather than nonspecific effects of tissue hypoxia.[67,69] The inhibition of CO to CYP enzymes is selective: in isolated perfused rabbit lung, CO inhibited the metabolism of p-nitroanisole but not of aniline,[69] whereas in human liver microsomes, CO inhibited CYP2D6 enzymes as shown by the inhibition of
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dextromethorphan O-demethylation and (+)-bufuralol 1′-hydroxylation, but not CYP2C or CYP3A activity.[68] However, the concentrations of CO used in those studies were much higher than those to which the average smoker is exposed to. Exposures were 7.5 to 60%[68,69] in these studies compared with 1000 to 1500 ppm (about 0.1%) delivered
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when smoking a cigarette. However, Montgomery and Rubin[66] achieved significant inhibition of hexobarbital clearance in rats with CO concentrations comparable with those to which smokers are exposed (1000 to 2500 ppm). We have recently found no effect of CO inhalation (resulting in levels similar to those achieved while smoking) on the metabolic clearance of caffeine (CYP1A2) or chlorzoxazone (CYP2E1).[54] Whether CO exposure from cigarette smoking might affect the metabolism of other drugs is unknown. 4. Heavy Metals Cigarette smoke contains trace amounts of heavy metals such as cadmium, nickel, chromium, lead and arsenic. Exposure to high doses of cadmium has been shown to decrease CYP2E1 levels and activity in rat liver, but had no effect on CYP3A4.[70] However, the dose of cadmium given to rats was 112 μg/kg,[70] whereas the amount of cadmium delivered in cigarette smoke is about 40 to 60ng per cigarette.[1] 5. Smoking and Drug Interactions As with drug-drug interactions, not all smoking-drug interactions are of clinical significance, i.e. they do not necessitate changes in the dose or drug. The number of clinically significant smokingdrug interactions is not very large (table I).[71,72] Most of the interactions are pharmacokinetic, mainly through the induction of drug-metabolising enzymes by cigarette smoke. Pharmacodynamic drug interactions with smoking (table II) are primarily explained by the pharmacological effects of nicotine, particularly its
Table II. Pharmacodynamic interactions between smoking and drugs Drug Benzodiazepines (diazepam, chlordiazepoxide) β-Blockers Opioids (dextropropoxyphene, pentazocine) Interaction Decreased sedation and drowsiness

cardiovascular effects.[73] Nicotine causes sympathetic neural stimulation through both central and peripheral mechanisms. Central mechanisms of sympathetic stimulation include activation of chemoreceptors and direct effects on the brain stem and spinal cord. Peripheral mechanisms include the release of catecholamines from the adrenal glands and vascular nerve endings. These effects are associated with increased levels of circulating catecholamines and, consequently, acute increases in the heart rate and blood pressure after cigarette smoking. Nicotine also causes coronary and cutaneous vasoconstriction. Cutaneous vasoconstriction results in a decrease in skin temperature.[74]
5.1 Theophylline

A number of studies have determined the effect of cigarette smoke on theophylline metabolism. Theophylline is metabolised by CYP1A2.[9,36] It has been shown that theophylline clearance is significantly increased (by 58 to 100%) and t1⁄2 significantly decreased (almost 2-fold) in smokers compared with nonsmokers.[75-78] In accordance with these changes in metabolism, adverse reactions to theophylline are almost twice as frequent in nonsmokers compared with heavy smokers.[79] Conversely, within 7 days of smoking cessation, theophylline clearance falls by 35%.[80] Thus, theophylline doses need to be adjusted when smokers are admitted to hospitals and are unable to smoke.
5.2 Caffeine

Caffeine is another CYP1A2 substrate.[9,36] Caffeine metabolism is induced by approximately 60 to 70% by cigarette smoke;[41,81] however, this induction is masked in alcoholic patients.[82]

Mechanism Probably CNS stimulation Probably deceased end-organ responsiveness resulting from sympathetic activation by nicotine Unknown

Less effective for blood pressure and heart rate reduction in smokers Decreased analgesic effect in smokers; higher doses needed to achieve analgesia

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5.3 Tacrine

5.5.2 Benzodiazepines

Tacrine is primarily metabolised by CYP1A2.[9] Tacrine metabolism is significantly induced by smoking; one study found that the t1⁄2 of tacrine was about 50% shorter in smokers compared with nonsmokers.[72,83] Product information states that mean tacrine plasma concentrations of smokers are about one-third those of nonsmokers.[84]
5.4 Paracetamol (Acetaminophen)

Paracetamol is metabolised to its reactive intermediate metabolite N-acetyl-p-aminobenzoquinone imine (NAPQI) partly by CYP2E1 and CYP1A2, and possibly also by CYP3A4.[85-87] However, no consistent effect of smoking on paracetamol metabolism was found.[78]
5.5 Psychoactive Drugs
5.5.1 Antidepressants

Smokers experience less sedation and drowsiness with diazepam and chlordiazepoxide compared with nonsmokers.[93] Most probably, the interaction is pharmacodynamic rather than pharmacokinetic, since various studies report no significant difference in the pharmacokinetic parameters of diazepam, lorazepam, midazolam and chlordiazepoxide between smokers and nonsmokers.[93-96] However, in one study cigarette smoking was associated with a significantly increased oral clearance of oxazepam, and in another study the Cmax was lower and t1⁄2 shorter for N-desmethyldiazepam after an oral dose of clorazepate in smokers compared with nonsmokers.[61,97]
5.5.3 Antipsychotics

Nortriptyline is not significantly affected by smoking. In one study,[88] there was no difference in steady-state concentrations (Css) of nortriptyline between smokers and nonsmokers; in another study, smokers had lower total concentrations of nortriptyline in plasma compared with nonsmokers, but there was no difference in free drug concentrations.[89] Imipramine plasma concentrations were lower in smokers compared with nonsmokers;[90] however, they were still within the therapeutic range, and the free concentrations were not measured. The clinical significance of this interaction remains unclear. The disposition kinetics of oral sustained release bupropion are similar in smokers and nonsmokers.[91] Fluvoxamine concentrations were found to be affected by cigarette smoking; smokers had significantly lower areas under the concentration-time curve (AUCs) and maximal serum concentrations (Cmax) compared with nonsmokers (771 ± 346 nmol/L • h and 39.1 ± 17.3 nmol/L vs 1110 ± 511 nmol/L • h and 57.7 ± 21.5 nmol/L, respectively). There was no significant difference in t1⁄2.[92] The probable mechanism is induction of CYP1A2.
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Chlorpromazine caused less drowsiness and orthostatic hypotension in smokers compared with nonsmokers. However, the AUC and Cmax of chlorpromazine were only slightly decreased in smokers (by 36% and 24%, respectively) and there was no correlation between symptoms and plasma concentrations.[98] There was significant variability of AUCs between individuals, both among smokers and nonsmokers, and with the small number of individuals it is difficult to draw a conclusion. In one case report, a patient with schizophrenia developed severe drowsiness on the same dose of chlorpromazine after he stopped smoking, with relief of symptoms after he resumed smoking. Plasma concentrations of chlorpromazine were about 3 times higher after quitting smoking compared with those while smoking.[99] It seems likely that both pharmacokinetic and pharmacodynamic interactions are involved. In a retrospective study, the Css and clearance of haloperidol were compared for 23 smokers and 27 nonsmokers; the group of smokers had significantly lower Css and higher haloperidol clearance.[100] The clinical significance is unclear, since haloperidol concentration in all patients was within the therapeutic limits. The atypical antipsychotics clozapine and olanzapine are metabolised by CYP1A2 and CYP2D6.[101-103] Clozapine plasma concentrations
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have been compared in smokers and nonsmokers. In one study smokers had a Css of 81.8% that of nonsmokers;[104] however, in another study there was no difference in clozapine concentrations between smokers and nonsmokers.[105] For olanzapine, clearance was 98% higher in healthy smokers compared with nonsmokers.[103]
5.6 Cardiovascular Drugs

β-Blockers were shown to be less effective for blood pressure and heart rate reduction in smokers compared with nonsmokers in 2 large trials of hypertension, as well as being less effective in preventing end-organ damage.[106,107] However, another trial of primary myocardial infarction prevention in patients with hypertension found no difference in benefit derived from β-blockers between smokers and nonsmokers.[108] This interaction may have a pharmacodynamic basis, since nicotine causes catecholamine release and increases blood pressure and heart rate. There may also be a pharmacokinetic basis for this interaction: the AUC of propranolol after a single dose was about 50% lower in 6 smokers compared with 7 nonsmokers, and its oral clearance increased by 77%.[60] The increase in clearance was because of an increase in side-chain oxidation and glucuronidation, while there was no increase in aromatic ring oxidation. There was no difference in t1⁄2 between smokers and nonsmokers; most likely the increase in oral clearance reflects the increase in first-pass metabolism. Interestingly, there was also an increase in renal clearance of the propranolol metabolite naphthoxylactic acid in smokers, though the pH of urine was not controlled.[60]
5.6.2 Antiarrhythmics

5.6.1 β-Blockers

pared with 5 nonsmokers, while there was no difference in systemic clearance, indicating an effect of smoking on the first-pass metabolism of lidocaine.[110] Likewise, the oral clearance of mexiletine was higher and t1⁄2 shorter in 6 smokers compared with 8 nonsmokers, with evidence of accelerated glucuronide conjugation and oxidative metabolism to hydroxymethylmexiletine, but no difference in oxidation to p-hydroxymexiletine.[58]
5.7 Anticoagulants
5.7.1 Warfarin

Warfarin clearance and Css were affected by smoking to a small degree in a crossover study of 9 smokers;[111] the increase in clearance and Css was about 13% during smoking, but did not have a measurable effect on prothrombin time.
5.7.2 Heparin

With heparin, the t1⁄2 was shorter and clearance faster in smokers.[112] The mechanism is likely to be an increase in the binding of heparin to antithrombin III, related to the prothrombotic effects of cigarette smoking. Thus, smokers may require higher doses of heparin compared with nonsmokers to achieve anticoagulation.
5.8 Steroid Hormones

A meta-analysis of pharmacokinetic studies with flecainide demonstrated that smokers had a significantly higher metabolic clearance of flecainide compared with nonsmokers, lower trough concentrations per dose, and required higher doses of flecainide to control their arrhythmia.[109] The oral clearance of lidocaine (lignocaine) was found to be significantly higher in 4 smokers com© Adis International Limited. All rights reserved.

No effect of smoking was found on the pharmacokinetics of prednisone, prednisolone and dexamethasone.[113] No effect of smoking was found on the Css of ethinylestradiol and levonorgestrel in women smokers on oral contraceptives compared with nonsmokers.[114] No effects of smoking on pharmacokinetics were found after a single dose of ethinylestradiol and levonorgestrel in women not taking oral contraceptives; however, in a small group of women taking oral contraceptives the clearance of ethinylestradiol was greater in smokers compared with nonsmokers.[115] In another study, a differential effect of smoking on estrogen metabolism was demonstrated: in cigarette smokers, 2-hydroxylation of estrogen (producing an inactive metabolite) was increased 2Clin Pharmacokinet 1999 Jun; 36 (6)

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fold compared with nonsmokers.[116] This may be an explanation for the anti-estrogenic effects of smoking, and may contribute to the increased risk of osteoporosis in women who smoke.
5.9 Insulin

ers.[126] However, smoking was found to induce the glucuronidation of codeine without affecting Oand N-demethylation.[127] 6. Conclusions Cigarette smoke contains several chemical constituents that can interact with drug-metabolising enzymes. The best characterised are polycyclic aromatic hydrocarbons that induce 3 isoforms of CYP: CYP1A1, CYP1A2 and possibly CYP2E1, and some isoforms of UDP-glucuronosyltransferase. These enzymes are important in drug metabolism and/or in the activation of procarcinogens, many of which are found in cigarette smoke. Much has been learned about the molecular mechanisms for this activation, particularly for CYP1A1 and CYP1A2. Although it is known that there are phenotypical differences in the inducibility of these enzymes, the sites of polymorphisms remain to be determined. This is of major importance to public health, as there is appears to be a link between the inducibility of carcinogen-activating enzymes and the risk of cancer, particularly lung cancer. Most of the clinically significant pharmacokinetic interactions with drugs occur through the induction of CYP1A2 – such as with caffeine, theophylline and tacrine. The effects of other major components of cigarette smoke, such as nicotine and carbon monoxide, on human drug metabolism in vivo, and the clinical significance of such interactions, are still to be determined. Pharmacodynamic interactions between cigarette smoking and psychoactive drugs, cardiovascular drugs and insulin have been reported. These interactions probably occur as a consequence of the stimulant actions of nicotine, both in the brain and on the cardiovascular system. Cigarette smoking needs to be considered in selecting individuals for clinical trials. Optimally, early clinical trials should compare drug metabolism, kinetics and effects in smokers and in nonsmokers and/or use cigarette smoking as a predictive variable in population kinetics/dynamics analyses that include cigarette smokers. This is parClin Pharmacokinet 1999 Jun; 36 (6)

The rate of absorption of insulin after subcutaneous injection is affected by subcutaneous blood flow.[117] Nicotine causes cutaneous vasoconstriction.[74] One study demonstrated a 113% decrease in the extent of insulin absorption during cigarette smoking and a 30% decrease in the 30 min after smoking.[118] However, it is unclear how this translates into clinical effects. There is some evidence that smokers require more insulin compared with nonsmokers;[119] on the other hand, there does not seem to be a significant difference in glycaemic control between smokers and nonsmokers.[120]
5.10 Alcohol (Ethanol)

The rate of absorption and Cmax of alcohol are significantly decreased by cigarette smoking.[121] There was a close correlation between the slowing of gastric emptying time and the AUC during cigarette smoking.[121]
5.11 Opioids
5.11.1 Dextropropoxyphene

Dextropropoxyphene was found to be a less effective analgesic in smokers compared with nonsmokers: 10% of nonsmokers did not have an effect versus 20.3% of heavy smokers.[122,123] The mechanism of the interaction between cigarette smoking and dextropropoxyphene is unknown.
5.11.2 Pentazocine

Pentazocine elimination in urine was reduced by 40% in smokers compared with nonsmokers, possibly indicating increased metabolic clearance.[124] Consistent with this finding, another study found that smokers required larger doses of pentazocine to achieve an analgesic effect.[125]
5.11.3 Codeine

Overall, the AUC, t1⁄2 and Cmax of codeine were not different in smokers compared with nonsmok© Adis International Limited. All rights reserved.

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ticularly important for drugs that are substrates for enzymes known to be induced by cigarette smoke, that is CYP1A1, 1A2, 2E1 and glucuronosyltransferases. As volunteers for clinical trials are often not truthful about their smoking behaviour, it is recommended that a screening test, such as measurement of the nicotine metabolite cotinine in blood, saliva or urine, be performed.[128] Acknowledgements
The authors thank Dr Deanna Kroetz for her critical review of the manuscript and Ms Kaye Welch for editorial assistance. Supported by US Public Health Service grants DA02277 and DA01696 from the National Institute on Drug Abuse, National Institutes of Health, and carried out in part at the General Clinical Research Center with the support of the Division of Research Resources, National Institutes of Health (RR–00083).

References
1. Hoffmann D, Djordjevic MV, Hoffmann I. The changing cigarette. Prev Med 1997; 26: 427-34 2. Schumacher JN, Green CR, Best FW, et al. An extensive investigation of the water-soluble portion of cigarette smoke. J Agric Food Chem 1977; 25: 310-20 3. Conney AH. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G.H.A. Clowes Memorial Lecture. Cancer Res 1982; 42: 4875-917 4. Guengerich FP, Shimada T, Iwasaki M, et al. Activation of carcinogens by human liver cytochromes P-450. Basic Life Sci 1990; 53: 381-96 5. Ikawa S, Uematsu F, Watanabe K, et al. Assessment of cancer susceptibility in humans by use of genetic polymorphisms in carcinogen metabolism. Pharmacogenetics 1995; 5 (Spec. No): S154-60 6. Gonzalez FJ. The molecular biology of cytochrome P450s. Pharmacol Rev 1988; 40: 243-88 7. Guengerich FP. Metabolic activation of carcinogens. Pharmacol Ther 1992; 54: 17-61 8. McManus ME, Burgess WM, Veronese ME, et al. Metabolism of 2-acetylaminofluorene and benzo(a)pyrene and activation of food-derived heterocyclic amine mutagens by human cytochromes P-450. Cancer Res 1990; 50: 3367-76 9. Wrighton SA, VandenBranden M, Ring BJ. The human drug metabolizing cytochromes P450. J Pharmacokinet Biopharm 1996; 24: 461-73 10. Denissenko MF, Pao A, Tang M, et al. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science 1996; 274: 430-2 11. Phillips DH, Hewer A, Martin CN, et al. Correlation of DNA adduct levels in human lung with cigarette smoking. Nature 1988; 336: 790-2 12. McLemore TL, Adelberg S, Liu MC, et al. Expression of CYP1A1 gene in patients with lung cancer: evidence for cigarette smoke-induced gene expression in normal lung tissue and for altered gene regulation in primary pulmonary carcinomas. J Natl Cancer Inst 1990; 82: 1333-9

13. Anttila S, Hietanen E, Vainio H, et al. Smoking and peripheral type of cancer are related to high levels of pulmonary cytochrome P450IA in lung cancer patients. Int J Cancer 1991; 47: 681-5 14. Kouri RE, McKinney CE, Slomiany DJ, et al. Positive correlation between high aryl hydrocarbon hydroxylase activity and primary lung cancer as analyzed in cryopreserved lymphocytes. Cancer Res 1982; 42: 5030-7 15. Catteau A, Douriez E, Beaune P, et al. Genetic polymorphism of induction of CYP1A1 (EROD) activity. Pharmacogenetics 1995; 5: 110-9 16. Willey JC, Coy EL, Frampton MW, et al. Quantitative RT-PCR measurement of cytochromes P450 1A1, 1B1, and 2B7, microsomal epoxide hydrolase, and NADPH oxidoreductase expression in lung cells of smokers and nonsmokers. Am J Respir Cell Mol Biol 1997; 17: 114-24 17. Murray BP, Edwards RJ, Murray S, et al. Human hepatic CYP1A1 and CYP1A2 content, determined with specific anti-peptide antibodies, correlates with the mutagenic activation of PhIP. Carcinogenesis 1993; 14: 585-92 18. Reyes H, Reisz-Porszasz S, Hankinson O. Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor. Science 1992; 256: 1193-5 19. Hoffmann EC, Reyes H, Chu FF, et al. Cloning of a factor required for activity of the Ah (dioxin) receptor. Science 1991; 252: 954-8 20. Kubota M, Sogawa K, Kaizu Y, et al. Xenobiotic responsive element in the 5′-upstream region of the human P450c gene. J Biochem (Tokyo) 1991; 110: 232-6 21. Swanson HI, Chan WK, Bradfield CA. DNA binding specificities and pairing rules of the Ah receptor, ARNT, and SIM proteins. J Biol Chem 1995; 270: 26292-302 22. Nebert DW. Drug metabolism and signal transduction: possible role of Ah receptor and arachidonic acid cascade in protection from ethanol toxicity. Experientia 1994; 71 Suppl.: 231-40 23. Nebert DW, Petersen DD, Puga A. Human AH locus polymorphism and cancer: inducibility of CYP1A1 and other genes by combustion products and dioxin. Pharmacogenetics 1991; 1: 68-78 24. Johnson BS, Brooks BA, Reyes H, et al. An MspI RFLP in the human ARNT gene, encoding a subunit of the nuclear form of the Ah (dioxin) receptor. Hum Mol Genet 1992; 1: 351 25. Jacquet M, Lambert V, Baudoux E, et al. Correlation between P450 CYP1A1 inducibility, MspI genotype and lung cancer incidence. Eur J Cancer 1996; 32A: 1701-6 26. Tefre T, Ryberg D, Haugen A, et al. Human CYP1A1 (cytochrome P(1)450) gene: lack of association between the MspI restriction fragment length polymorphism and incidence of lung cancer in a Norwegian population. Pharmacogenetics 1991; 1: 20-5 27. Rannug A, Alexandrie AK, Persson I, et al. Genetic polymorphism of cytochromes P450 1A1, 2D6 and 2E1: regulation and toxicological significance. J Occup Environ Med 1995; 37: 25-36 28. Raunio H, Husgafvel Pursiainen K, Anttila S, et al. Diagnosis of polymorphisms in carcinogen-activating and inactivating enzymes and cancer susceptibility: a review. Gene 1995; 159: 113-21 29. Nakachi K, Imai K, Hayashi S, et al. Genetic susceptibility to squamous cell carcinoma of the lung in relation to cigarette smoking dose. Cancer Res 1991; 51: 5177-80 30. Kawajiri K, Nakachi K, Imai K, et al. The CYP1A1 gene and cancer susceptibility. Crit Rev Oncol Hematol 1993; 14: 77-87

© Adis International Limited. All rights reserved.

Clin Pharmacokinet 1999 Jun; 36 (6)

436

Zevin & Benowitz

31. Hayashi S, Watanabe J, Nakachi K, et al. Genetic linkage of lung cancer-associated MspI polymorphisms with amino acid replacement in the heme binding region of the human cytochrome P450IA1 gene. J Biochem Tokyo 1991; 110: 407-11 32. Nimura Y, Yokoyama S, Fujimori M, et al. Genotyping of the CYP1A1 and GSTM1 genes in esophageal carcinoma patients with special reference to smoking. Cancer 1997; 80: 852-7 33. Hayashi S, Watanabe J, Kawajiri K. High susceptibility to lung cancer analyzed in terms of combined genotypes of P450IA1 and Mu-class glutathione S-transferase genes. Jpn J Cancer Res 1992; 83: 866-70 34. Ishibe N, Wiencke JK, Zuo ZF, et al. Susceptibility to lung cancer in light smokers associated with CYP1A1 polymorphisms in Mexican- and African-Americans. Cancer Epidemiol Biomarkers Prev 1997; 6: 1075-80 35. Sugimura H, Hamada GS, Suzuki I, et al. CYP1A1 and CYP2E1 polymorphism and lung cancer, case-control study in Rio de Janeiro, Brazil. Pharmacogenetics 1995; 5 Spec. No.: S145-8 36. Meyer UA. Overview of enzymes of drug metabolism. J Pharmacokinet Biopharm 1996; 24: 449-59 37. Eaton DL, Gallagher EP, Bammler TK, et al. Role of cytochrome P4501A2 in chemical carcinogenesis: implications for human variability in expression and enzyme activity. Pharmacogenetics 1995; 5: 259-74 38. Quattrochi LC, Tukey RH. The human cytochrome CYP1A2 gene contains regulatory elements responsive to 3-methylcholanthrene. Mol Pharmacol 1989; 36: 66-71 39. Quattrochi LC, Vu T, Tukey RH. The human cytochrome CYP1A2 gene and induction by 3-methylcholanthrene. A region of DNA that supports AH-receptor binding and promoter-specific induction. J Biol Chem 1994; 269: 6949-54 40. Butler MA, Lang NP, Young JF, et al. Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites. Pharmacogenetics 1992; 2: 116-27 41. Kalow W, Tank BK. Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol Ther 1991; 50: 508-19 42. Tang BK, Kalow W. Assays for CYP1A2 by testing in vivo metabolism of caffeine in humans. Methods Enzymol 1996; 272: 124-31 43. Schweikl H, Taylor JA, Kitareewan S, et al. Expression of CYP1A1 and CYP1A2 genes in human liver. Pharmacogenetics 1993; 3: 239-49 44. Nakajima M, Yokoi T, Mizutani M, et al. Phenotyping of CYP1A2 in Japanese population by analysis of caffeine urinary metabolites: absence of mutation prescribing the phenotype in the CYP1A2 gene. Cancer Epidemiol Biomarkers Prev 1994; 3: 413-21 45. Fuhr U, Rost KL. Simple and reliable CYP1A2 phenotyping by the paraxanthine/caffeine ratio in plasma and in saliva. Pharmacogenetics 1994; 4: 109-16 46. Guengerich FP, Kim DH, Iwasaki M. Role of human cytochrome P450 IIE1 in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol 1991; 4: 168-79 47. Girre C, Lucas D, Hispard E, et al. Assessment of cytochrome P4502E1 induction in alcoholic patients by chlorzoxazone pharmacokinetics. Biochem Pharmacol 1994; 47: 1503-8 48. Lucas D, Menez C, Girre C, et al. Cytochrome P450 2E1 genotype and chlorzoxazone metabolism in healthy and alcoholic Caucasian subjects. Pharmacogenetics 1995; 5: 298-304 49. O’Shea D, Davis SN, Kim RB, et al. Effect of fasting and obesity in humans on the 6-hydroxylation of chlorzoxazone: a

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63. 64.

65.

66.

67.

putative probe of CYP2E1 activity. Clin Pharmacol Ther 1994; 56: 359-67 Uematsu F, Kikuchi H, Motomiya M, et al. Human cytochrome P450IIE1 gene: DraI polymorphism and susceptibility to cancer. Tohoku J Exp Med 1992; 168: 113-7 Villard PH, Seree EM, Lacarelle B, et al. Effect of cigarette smoke on hepatic and pulmonary cytochromes P450 in mouse: evidence for CYP2E1 induction in lung. Biochem Biophys Res Commun 1994; 202: 1731-7 Villard PH, Herber R, Seree E, et al. Effect of cigarette smoke on UDP-glucuronosyltransferase activity and cytochrome P450 content in liver, lung and kidney microsomes in mice. Pharmacol Toxicol 1998; 82: 74-9 Seree EM, Villard PH, Re JL, et al. High inducibility of mouse renal CYP2E1 gene by tobacco smoke and its possible effect on DNA single strand breaks. Biochem Biophys Res Commun 1996; 219: 429-34 Benowitz NL, Jacob III P, Saunders S, et al. Carbon monoxide, cigarette smoking and CYP2E1 activity [abstract]. Clin Pharmacol Ther 1999; 63: 154 Burchell B, Brierley CH, Rance D. Specificity of human UDPglucuronosyltransferases and xenobiotic glucuronidation. Life Sci 1995; 57: 1819-31 Bock KW, Frohling W, Remmer H, et al. Effects of phenobarbital and 3-methylcholanthrene on substrate specificity of rat liver microsomal UDP-glucuronyltransferase. Biochim Biophys Acta 1973; 327: 46-56 Fleischmann R, Remmer H, Starz U. Induction of cytochrome P-448 isoenzymes and related glucuronyltransferases in the human liver by cigarette smoking. Eur J Clin Pharmacol 1986; 30: 475-80 Grech Belanger O, Gilbert M, Turgeon J, et al. Effect of cigarette smoking on mexiletine kinetics. Clin Pharmacol Ther 1985; 37: 638-43 Bock KW, Schrenk D, Forster A, et al. The influence of environmental and genetic factors on CYP2D6, CYP1A2 and UDP-glucuronosyltransferases in man using sparteine, caffeine and paracetamol as probes. Pharmacogenetics 1994; 4: 209-18 Walle T, Walle UK, Cowart TD, et al. Selective induction of propranolol metabolism by smoking: additional effects on renal clearance of metabolites. J Pharmacol Exp Ther 1987; 241: 928-33 Ochs HR, Greenblatt DJ, Otten H. Disposition of oxazepam in relation to age, sex and cigarette smoking. Klin Wochenschr 1981; 59: 899-903 Benowitz NL, Jacob III P. Nicotine and cotinine elimination pharmacokinetics in smokers and nonsmokers. Clin Pharmacol Ther 1993; 53: 316-23 Zevin S, Jacob III P, Benowitz NL. Cotinine effects on nicotine metabolism. Clin Pharmacol Ther 1997; 61: 649-54 Anandatheerthavarada HK, Williams JF, Wecker L. The chronic administration of nicotine induces cytochrome P450 in rat brain. J Neurochem 1993; 60: 1941-4 Anandatheerthavarada HK, Williams JF, Wecker L. Differential effect of chronic nicotine administration on brain cytochrome P4501A1/2 and P4502E1. Biochem Biophys Res Commun 1993; 194: 312-8 Montgomery MR, Rubin RJ. The effect of carbon monoxide inhalation on in vivo drug metabolism in the rat. J Pharmacol Exp Ther 1971; 179: 465-73 Takano T, Motohashi Y, Miyazaki Y. Direct effect of carbon monoxide on hexo-barbital metabolism in the isolated per-

© Adis International Limited. All rights reserved.

Clin Pharmacokinet 1999 Jun; 36 (6)

Tobacco Smoking and Drug Interactions

437

68.

69.

70.

71. 72. 73.

74.

75.

76. 77.

78.

79.

80.

81.

82.

83.

84. 85.

86.

87.

fused liver in the absence of hemoglobin. J Toxicol Environ Health 1985; 15: 847-54 Leemann T, Bonnabry P, Dayer P. Selective inhibition of major drug metabolizing cytochrome P450 isozymes in human liver microsomes by carbon monoxide. Life Sci 1994; 54: 951-6 Trela BA, Carlson GP, Mayer PR. Effect of carbon monoxide on the cytochrome P-450-mediated metabolism of aniline and p-nitroanisol in the isolated perfused rabbit lung. J Toxicol Environ Health 1989; 27: 331-40 Alexidis AN, Rekka EA, Kourounakis PN. Influence of mercury and cadmium intoxication on hepatic microsomal CYP2E and CYP3A subfamilies. Res Commun Mol Pathol Pharmacol 1994; 85: 67-72 Miller LG. Cigarettes and drug therapy: pharmacokinetic and pharmacodynamic considerations. Clin Pharm 1990; 9: 125-35 Schein JR. Cigarette smoking and clinically significant drug interactions. Ann Pharmacother 1995; 29: 1139-48 Benowitz NL, Gourlay SG. Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy. J Am Coll Cardiol 1997; 29: 1422-31 Benowitz NL, Jacob III P, Jones RT, et al. Interindividual variability in the metabolism and cardiovascular effects of nicotine in man. J Pharmacol Exp Ther 1982; 221: 368-72 Powell JR, Thiercelin JF, Vozeh S, et al. The influence of cigarette smoking and sex on theophylline disposition. Am Rev Respir Dis 1977; 116: 17-23 Hunt SN, Jusko WJ, Yurchak AM. Effect of smoking on theophylline disposition. Clin Pharmacol Ther 1976; 19: 546-51 Jusko WJ, Schentag JJ, Clark JH, et al. Enhanced biotransformation of theophylline in marihuana and tobacco smokers. Clin Pharmacol Ther 1978; 24: 405-10 Miller LG. Recent developments in the study of the effects of cigarette smoking on clinical pharmacokinetics and clinical pharmacodynamics. Clin Pharmacokinet 1989; 17: 90-108 Pfeifer HF, Greenblatt DJ. Clinical toxicity of theophylline in relation to cigarette smoking: a report from the Boston Collaborative Drug Surveillance Program. Chest 1978; 73: 229-33 Lee BL, Benowitz NL, Jacob III P. Cigarette abstinence, nicotine gum, and theophylline disposition. Ann Intern Med 1987; 106: 553-5 Vistisen K, Loft S, Poulsen HE. Cytochrome P450 IA2 activity in man measured by caffeine metabolism: effect of smoking, broccoli and exercise. Adv Exp Med Biol 1991; 283: 407-11 Rizzo N, Hispard E, Dolbeault S, et al. Impact of long-term ethanol consumption on CYP1A2 activity. Clin Pharmacol Ther 1997; 62: 505-9 Welty D, Pool W, Woolf T, et al. The effect of smoking on the pharmacokinetics and metabolism of Cognex in healthy volunteers [abstract]. Pharm Res 1993; 10: S334 Cognex product information. In: Physician’s desk reference. Montvale (NJ): Medical Economics, 1995: 1828 Raucy JL, Lasker JM, Lieber CS, et al. Acetaminophen activation by human liver cytochromes P450IIE1 and P450IA2. Arch Biochem Biophys 1989; 271: 270-83 Snawder JE, Roe AL, Benson RW, et al. Loss of CYP2E1 and CYP1A2 activity as a function of acetaminophen dose: relation to toxicity [published erratum appears in Biochem Biophys Res Commun 1995; 206: 437]. Biochem Biophys Res Commun 1995; 203: 532-9 Thummel KE, Lee CA, Kunze KL, et al. Oxidation of acetaminophen to N-acetyl-p-aminobenzoquinone imine by human CYP3A4. Biochem Pharmacol 1993; 45: 1563-9

88. Norman TR, Burrows GD, Maguire KP, et al. Cigarette smoking and plasma nortriptyline levels. Clin Pharmacol Ther 1977; 21: 453-6 89. Perry PJ, Browne JL, Prince RA, et al. Effects of smoking on nortriptyline plasma concentrations in depressed patients. Ther Drug Monit 1986; 8: 279-84 90. Perel JM, Hurwic MJ, Kanzler MB. Pharmacodynamics of imipramine in depressed patients. Psychopharmacol Bull 1975; 11: 16-8 91. Hsyu P-H, Singh A, Giargiari TD, et al. Pharmacokinetics of bupropion and its metabolites in cigarette smokers versus nonsmokers. J Clin Pharmacol 1997; 37: 737-43 92. Spigset O, Carleborg L, Hedenmalm K, et al. Effect of cigarette smoking on fluvoxamine pharmacokinetics in humans. Clin Pharmacol Ther 1995; 58: 399-403 93. Boston Collaborative Drug Surveillance Program. Clinical depression of the central nervous system due to diazepam and chlordiazepoxide in relation to cigarette smoking and age. N Engl J Med 1973; 288: 277-80 94. Ochs HR, Greenblatt DJ, Burstein ES. Lack of influence of cigarette smoking on triazolam pharmacokinetics. Br J Clin Pharmacol 1987; 23: 759-63 95. Desmond PV, Roberts RK, Wilkinson GR, et al. No effect of smoking on metabolism of chlordiazepoxide [letter]. N Engl J Med 1979; 300: 199-200 96. Ochs HR, Greenblatt DJ, Knuchel M. Kinetics of diazepam, midazolam, and lorazepam in cigarette smokers. Chest 1985; 87: 223-6 97. Norman TR, Fulton A, Burrows GD, et al. Pharmacokinetics of N-desmethyldiazepam after a single oral dose of clorazepate: the effect of smoking. Eur J Clin Pharmacol 1981; 21: 229-33 98. Pantuck EJ, Pantuck CB, Anderson KE, et al. Cigarette smoking and chlorpromazine disposition and actions. Clin Pharmacol Ther 1982; 31: 533-8 99. Stimmel GL, Falloon IR. Chlorpromazine plasma levels, adverse effects, and tobacco smoking: case report. J Clin Psychiatry 1983; 44: 420-2 100. Jann MW, Saklad SR, Ereshefsky L, et al. Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance. Psychopharmacology (Berl) 1986; 90: 468-70 101. Taylor D. Pharmacokinetic interactions involving clozapine. Br J Psychiatry 1997; 171: 109-12 102. Ring BJ, Catlow J, Lindsay TJ, et al. Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine. J Pharmacol Exp Ther 1996; 276: 658-66 103. Fulton B, Goa KL. Olanzapine: a review of its pharmacological properties and therapeutic efficacy in the management of schizophrenia and related psychoses. Drugs 1997; 53: 281-98 104. Haring C, Meise U, Humpel C, et al. Dose-related plasma levels of clozapine: influence of smoking behaviour, sex and age. Psychopharmacology (Berl) 1989; 99 Suppl.: S38-S40 105. Hasegawa M, Gutierrez Esteinou R, Way L, et al. Relationship between clinical efficacy and clozapine concentrations in plasma in schizophrenia: effect of smoking. J Clin Psychopharmacol 1993; 13: 383-90 106. Buhler FR, Vesanen K, Watters JT, et al. Impact of smoking on heart attacks, strokes, blood pressure control, drug dose, and quality of life aspects in the International Prospective Primary Prevention Study in Hypertension. Am Heart J 1988; 115: 282-8 107. Bolli P, Buhler FR, McKenzie JK. Smoking, antihypertensive treatment benefit, and comprehensive antihypertensive treat-

© Adis International Limited. All rights reserved.

Clin Pharmacokinet 1999 Jun; 36 (6)

438

Zevin & Benowitz

108.

109.

110.

111. 112.

113.

114.

115.

116.

117.

118.

ment approach: some thoughts on the results of the International Prospective Primary Prevention Study in Hypertension. J Cardiovasc Pharmacol 1990; 16 Suppl.: S77-S80 Wilhelmsen L, Berglund G, Elmfeldt D, et al. Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. J Hypertens 1987; 5: 561-2 Holtzman JL, Weeks CE, Kvam DC, et al. Identification of drug interactions by meta-analysis of premarketing trials: the effect of smoking on the pharmacokinetics and dosage requirements for flecainide acetate. Clin Pharmacol Ther 1989; 46: 1-8 Huet PM, Lelorier J. Effects of smoking and chronic hepatitis B on lidocaine and indocyanine green kinetics. Clin Pharmacol Ther 1980; 28: 208-15 Bachmann K, Shapiro R, Fulton R, et al. Smoking and warfarin disposition. Clin Pharmacol Ther 1979; 25: 309-15 Cipolle RJ, Seifert RD, Neilan BA, et al. Heparin kinetics: variables related to disposition and dosage. Clin Pharmacol Ther 1981; 29: 387-93 Rose JQ, Yurchak AM, Meikle AW, et al. Effect of smoking on prednisone, prednisolone, and dexamethasone pharmacokinetics. J Pharmacokinet Biopharm 1981; 9: 1-14 Crawford FE, Back DJ, Orme ML, et al. Oral contraceptive steroid plasma concentrations in smokers and nonsmokers. BMJ (Clin Res Ed) 1981; 282: 1829-30 Kanarkowski R, Tornatore KM, Gardner MJ, et al. Pharmacokinetics of single and multiple doses of ethinyl estradiol and levonorgestrel in relation to smoking. Clin Pharmacol Ther 1988; 43: 23-31 Michnovicz JJ, Hershcopf RJ, Naganuma H, et al. Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking. N Engl J Med 1986; 315: 1305-9 Kolendorf K, Bojsen J, Nielsen SL. Adipose tissue blood flow and insulin disappearance from subcutaneous tissue. Clin Pharmacol Ther 1979; 25: 598-604 Klemp P, Staberg B, Madsbad S, et al. Smoking reduces insulin absorption from subcutaneous tissue. BMJ 1982; 284: 237

119. Madsbad S, McNair P, Christensen MS, et al. Influence of smoking on insulin requirement and metabolic status in diabetes mellitus. Diabetes Care 1980; 3: 41-3 120. Mathiesen ER, Soegaard U, Christiansen JS. Smoking and glycaemic control in male insulin dependent (type 1) diabetics. Diabetes Res 1984; 1: 155-7 121. Johnson RD, Horowitz M, Maddox AF, et al. Cigarette smoking and rate of gastric emptying: effect on alcohol absorption. BMJ 1991; 302: 20-3 122. Decreased clinical efficacy of propoxyphene in cigarette smokers. Clin Pharmacol Ther 1973; 14: 259-63 123. Jick H. Smoking and clinical drug effects. Med Clin North Am 1974; 58: 1143-9 124. Vaughan DP, Beckett AH, Robbie DS. The influence of smoking on the intersubject variation in pentazocine elimination. Br J Clin Pharmacol 1976; 3: 279-83 125. Keeri-Szanto M, Pomeroy JR. Atmospheric pollution and pentazocine metabolism. Lancet 1971; I (7706): 947-9 126. Rogers JF, Findlay JW, Hull JH, et al. Codeine disposition in smokers and nonsmokers. Clin Pharmacol Ther 1982; 32: 218-27 127. Yue QY, Tomson T, Sawe J. Carbamazepine and cigarette smoking induce differentially the metabolism of codeine in man. Pharmacogenetics 1994; 4: 193-8 128. Apseloff G, Ashton HM, Friedman H, et al. The importance of measuring cotinine levels to identify smokers in clinical trials. Clin Pharmacol Ther 1994; 56: 460-2

Correspondence and reprints: Dr Neal L. Benowitz, Division of Clinical Pharmacology and Experimental Therapeutics, San Francisco General Hospital Medical Center, Building 30, Room 3220, 1001 Potrero Avenue, San Francisco, CA 94110, USA. E-mail: [email protected]

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Clin Pharmacokinet 1999 Jun; 36 (6)