Effects of tobacco smoking and oral contraceptive use on theophylline disposition.

Abstract

1 The independent as well as interactive effects of chronic (> 6 months) oral contraceptive (OC) use and cigarette smoking on single-dose (4 mg/kg) theophylline disposition were assessed in 49 young, healthy women. 2 Significant elevations (40%) in theophylline plasma clearance were found in women who smoked. OC use resulted in decreases in clearance of a similar magnitude (28%). These factors do not appear to interact with respect to theophylline disposition. The combination of main effects tended to cancel one another (clearance of49.1 ml h-I kg-'ideal body weight for OC non-user, non-smoker, vs 49.7 ml h-' kg-'for OC user-smoker). 3 Single dose exposure to OC in non-users did not significantly alter theophylline pharmacokinetics for the group as a whole. However, in the subgroup of smoking subjects, significant decreases in clearance were evident (P < 0.05). Analogous results were found for half-life. Volume of distribution was slightly diminished in smokers, but was unaffected in OC users.4 Areas under the serum concentration-time (AUC) profiles of norgestrel and ethinyloestradiol were examined in 27 women as indices of OC exposure. The smallest values of theophylline clearance were found in the subjects with largest AUC of both OC steroids. 5 Appropriate statistical analyses of data which are influenced by multiple factors are discussed.Special concern is needed when the factor partitioning process yields subgroups of unequal sizes.

Differential Effect of Cigarette Smoking on Antipyrine Oxidation versus Acetaminophen Conjugation

“…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.…”

Use of Three Probes to Assess the Influence of Sex on Hepatic Drug Metabolism

“…There is a variable influence of OCS drugs on the clearance of benzodiaze pines [5,22]. Theophylline clearance is de creased by OCS use [23] as is antipyrine clearance [24]. On the other hand, OCS use tends to increase acetaminophen clearance [5] and this is a manifestation of both in creased oxidation and glucuronidation [20], It is clear that one or two probes of hepatic drug-metabolizing enzyme activity cannot provide good predictions about the impact of OCS use on drug metabolism.…”

Theophylline and antipyrine disposition in smoking and non‐smoking epileptic subjects.

“…The identification of many of these factors has resulted from carefully controlled studies where other extrinsic factors are minimised. Investigations into dual factors have recently been carried out; for example the inhibitory effects of cimetidine (Grygiel et al, 1984) and oral contraceptives (Gardner et al, 1983) have been compared in smokers and nonsmokers. These studies have demonstrated how two opposing effects may cancel out changes in clearance, and hence no net effect is observed.…”