Effects of tobacco smoking and oral contraceptive use on theophylline disposition

Abstract

The independent as well as interactive effects of chronic (greater than 6 months) oral contraceptive (OC) use and cigarette smoking on single-dose (4 mg/kg) theophylline disposition were assessed in 49 young, healthy women. 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 of 49.1 ml h-1 kg-1 ideal body weight for OC non-user, non-smoker, vs 49.7 ml h-1 kg-1 for OC user-smoker). 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 less than 0.05). Analogous results were found for half-life. Volume of distribution was slightly diminished in smokers, but was unaffected in OC users. 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. 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.

PIP: The independent and interactive effects of smoking and oral contraceptive (OC) use on theophylline disposition were examined in 49 healthy women aged 19-30 years. 16 subjects had used OCs for longer than 6 months, and 27 reported daily tobacco use. Subjects were subdivided into 4 groups based on their tobacco and OC use or nonuse. A single dose of theophylline (4 mg/kg) was administered orally and venous blood samples were collected 0, 0.5, 1, 2, 3, 5, 7, 11, and 23 hours later. For 27 subjects, a single Ovral tablet was given 1 hour before the test dose of aminophylline. For 16 subjects, this treatment represented a single dose exposure, whereas for 11 the tablet was their routine daily OC. A 4-way analysis of covariance was performed, with the main effects defined as cigarette smoking, OC use, marijuana use, and acute exposure to contraceptive steroids. Cigarette smoking, chronic OC ingestion, and daily caffeine intake significantly altered theophylline clearance processes, while casual marijuana use and acute OC exposure failed to induce significant changes in this parameter. A 40% elevation in theophylline clearance was observed in women who smoked, while OC use resulted in a 28% decrease in clearance. These factors did not appear to interact with respect to theophylline disposition, and the combination of main effects tended to cancel one another. When areas under the serum concentration-time (AUC) profiles of norgestrel and ethinylestradiol were examined in the 27 women with experimental OC exposure, the smallest values of theophylline clearance were found in the subjects with largest AUC of both OC steroids. Data suggest that OC use exerts a significant inhibitory effect on theophylline clearance, while cigarette smoking markedly enhances theophylline's hepatic metabolism. The most likely explanation for the inhibitory effect of OC use is that chronic exposure to steroidal agents reduces the nonconjugative activities of the liver. A limitation of the study is that partitioning of the study group by mulitple factors resulted in subgroups of unequal size.