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

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.