Kinetics of Diazepam, Midazolam, and Lorazepam in Cigarette Smokers

Ochs, Hermann R.; Greenblatt, David J.; Knüchel, Martin

doi:10.1378/chest.87.2.223

Cited by 41 publications

(12 citation statements)

References 20 publications

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“…Results from several in vivo studies suggest that the clearance of acetaminophen (Bock et al, 1994; Bock et al, 1987), oxazepam (Ochs et al, 1981), and codeine (Yue et al, 1989; Yue et al, 1994) is higher in cigarette smokers, although the extent of the difference was small and probably clinically unimportant. In contrast, results of several other studies show no effects of smoking on the clearance by glucuronidation of acetaminophen (Miners et al, 1984; Scavone et al, 1990), diflunisal (Macdonald et al, 1990), and lorazepam (Ochs et al, 1985). …”

Section: Interindividual Variability In Activity Of the Major Ugt Isomentioning

confidence: 63%

Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system

Court¹

2009

Drug Metabolism Reviews

182

147

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The human liver bank has provided an invaluable model system for the study of interindividual variability in expression and activity of the major hepatic UGTs, including UGT1A1, 1A4, 1A6, 1A9, 2B7, and 2B15. Based on studies using UGT isoform selective probes, the rank order of activity variability is UGT 1A1 > 1A6 > 2B15 > 1A4 = 1A9 > 2B7 with coefficient of variation values ranging from 92% to 45%. Liver donor age, sex, enzyme inducers, and genetic polymorphism are factors that have been implicated as sources of this variability in UGT activity. The expression of UGTs prior to and immediately following birth is quite limited, explaining the susceptibility of neonates to certain drug toxicities. Old age appears to have minimal effect on UGT function. Sex differences in UGT activity are relatively small and are confined to several UGTs, including UGT2B15, which shows higher activity in males compared with females. Enzyme inducers, including co-administered drugs, smoking, and alcohol may increase hepatic UGT levels. Human liver bank phenotype-genotype studies using UGT isoform-selective probes have identified common genetic polymorphisms that are predictive of glucuronidation activity in vitro that were subsequently verified as predictors of probe drug clearance by glucuronidation in vivo.

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Section: Interindividual Variability In Activity Of the Major Ugt Isomentioning

confidence: 63%

Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system

Court¹

2009

Drug Metabolism Reviews

182

147

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“…Bock et al [1987] found an increased urinary ex cretion ratio of intact acetaminophen di vided by acetaminophen metabolites, but the plasma clearance of acetaminophen was not evaluated. The benzodiazepine deriva tives, oxazepam and lorazepam, are biotransformed mainly by glucuronide conjuga tion , Ochs et al [1981] found significantly enhanced clearance of oxazepam among cigarette smokers, but this was not true for lorazepam [Ochs et al, 1985],…”

Section: Discussionmentioning

confidence: 96%

“…The hydrocarbons contained in tobacco smoke induce hepatic microsomal drug-me tabolizing enzymes, causing an enhanced clearance of a number of drugs in cigarette smokers as compared to nonsmoking control subjects [Murphy et al, 1988;Vestal et al, 1975;Loft et al, 1988;Gardner et al, 1983;Cusack et al, 1985], However, the inducing effects of smoking are not observed for all drugs [Acheson et al, 1987;Ochs et al, 1985Ochs et al, , 1986Ochs et al, , 1987Schaaf et al, 1987], We evaluated the influence of cigarette smoking on the kinetics of single intravenous doses of antipyrine and acetaminophen. Since the studies were performed in the same labora tory using similar (and in some cases identi cal) groups of subjects, differential effects of smoking on the kinetics of the two drugs are unlikely to be attributable to interlaboratory méthodologie differences, or to different characteristics of the study populations.…”

Section: Discussionmentioning

confidence: 99%

“…1982;D'Arcy, 1984;Miller, 1989]. Some studies also suggest a reduced drug effect or the need to increase drug dosage in cigarette smoking populations as compared to nonsmokers [Jick, 1974;Miller, 1977], How ever, the altered drug disposition by ciga rette smoking is not uniformly reported, and some studies show a small or negligible in fluence of smoking [Acheson et al, 1987;Ochs et al, 1985Ochs et al, , 1986Ochs et al, , 1987, Antipyrine and acetaminophen have been used as marker compounds to evaluate drugmetabolizing activity. Antipyrine is bio transformed by a series of parallel oxidative mechanisms, leading to three principal me tabolites formed by déméthylation and/or hydroxylation [Danhof et al, 1982;Eichelbaum et al, 1983;Boobis et al, 1981].…”

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confidence: 99%

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Differential Effect of Cigarette Smoking on Antipyrine Oxidation versus Acetaminophen Conjugation

et al. 1990

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The effect of cigarette smoking on drug oxidation and conjugation was studied using antipyrine and acetaminophen as marker compounds. For the antipyrine study, healthy cigarette smokers (n = 30) and nonsmoking controls (n = 53) received a single 1.0-gram intravenous dose of antipyrine. For the acetaminophen study, 14 smokers and 15 nonsmokers received a 650-mg intravenous dose of acetaminophen. The clearance of antipyrine was significantly increased (0.93 vs. 0.60 ml/min/kg, p < 0.0001) and elimination half-life was correspondingly reduced (8.9 vs. 13.0 h, p < 0.0001) in smokers compared to nonsmoking controls. Total recovery of antipyrine and metabolites excreted in urine did not differ between groups, but there was a significantly increased fractional clearance of antipyrine via formation of 4-hydroxyantipyrine and 3-hydroxymethyl metabolites in smokers. Fractional clearance via formation of norantipyrine did not differ significantly between groups. Comparison of acetaminophen kinetics between smokers and nonsmokers indicated no significant differences in elimination half-life, clearance or volume of distribution. Thus, cigarette smoking is more likely to induce drug oxidation rather than drug conjugation. However, not all oxidative pathways are equally influenced; induction effects of smoking are highly substrate selective and pathway specific.

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“…Cigarette smoking stimulates the metabolism of a number of drugs, leading to increased clearance and reduced steady-state plasma concentrations during multiple dosage (Dawson & Vestal, 1982;Jusko, 1978Jusko, , 1979 (Norman et al, 1981) and oxazepam (Ochs et al, 1981) among cigarette smokers, but other studies of diazepam, lorazepam, midazolam, desmethyldiazepam, ahd alprazolam, which were designed specifically to evaluate the effects of smoking as such, have indicated that smoking has no clinically important effects on the clearance of these drugs (Ochs et al, 1985(Ochs et al, , 1986Smith et al, 1983b All subjects received a single 0.5 mg dose of triazolam with 100-200 ml of tap water following an overnight fast. They remained fasting until 3 h after the dose.…”

Section: Introductionmentioning

confidence: 99%

Lack of influence of cigarette smoking on triazolam pharmacokinetics.

Ochs

Burstein

1987

Brit J Clinical Pharma

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The influence of cigarette smoking on the pharmacokinetics of a single dose of the triazolobenzodiazepine hypnotic triazolam was evaluated in 12 healthy nonsmoking male volunteers and in 12 male subjects, matched for age, height and weight, who smoked an average of 24 cigarettes a day (range: 15‐30). Triazolam kinetics were determined from multiple serum concentrations measured during 15 h after a single 0.5 mg dose. There were no significant differences between nonsmoking controls and cigarette smokers in the peak serum triazolam concentration (4.64 vs 4.73 ng ml‐1), the time of peak concentration (0.98 vs 1.0 h after dosage), elimination half‐life (2.8 vs 2.5 h), or oral clearance of triazolam (506 vs 627 ml min‐1). Likewise there were no significant differences between groups in the extent of triazolam binding to serum protein (18.8 vs 18.5% unbound). Altered pharmacodynamics of triazolam in cigarette smokers are not likely to be explained by altered pharmacokinetics.

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Kinetics of Diazepam, Midazolam, and Lorazepam in Cigarette Smokers

Cited by 41 publications

References 20 publications

Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system

Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system

Differential Effect of Cigarette Smoking on Antipyrine Oxidation versus Acetaminophen Conjugation

Lack of influence of cigarette smoking on triazolam pharmacokinetics.

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