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.

The effect of chronic oral contraceptive (OC) usage on the disposition of theophylline was examined. Aminophylline solution (4 mg/kg) was given orally to 8 healthy female non-OC users and to 8 healthy women who were chronic (greater than 6 months) OC users. The OC user group had a significantly lower total plasma clearance of theophylline than women not using OC (35.1 +/- 5.6 vs. 53.1 +/- 14.5 ml/h/kg). The t1/2 was also significantly prolonged in the OC group (9.79 +/- 1.43 vs. 7.34 +/- 1.75 h) while the volume of distribution was similar between the 2 groups. The serum ethinylestradiol (EE) concentrations after oral OC administration were measured simultaneously. The apparent clearance of EE was about 30% lower in the OC users. A significant positive correlation was found between the apparent clearance of EE and the plasma clearance of theophylline. The effects of OC are predominantly due to chronic use with decreased elimination of both theophylline and EE.

The effects of tobacco and oral contraceptive (OC) use (Ovral) on the pharmacokinetics of levonorgestrel (0.25 mg) and ethinyl estradiol (50 micrograms) were examined. Young women (n = 27) were grouped as follows: I: non-OC users/nonsmokers; II: OC users/nonsmokers; III: non-OC users/smokers; and IV: OC users/smokers. The apparent clearance of levonorgestrel in group I was 80.9 +/- 15.6 ml/hr/kg and the half-life was 19.3 hours. A significant decrease in levonorgestrel clearance was seen in the chronic OC users (groups II and IV). The apparent oral clearance of ethinyl estradiol was 1002 +/- 398 ml/hr/kg in group I and the half-life averaged 7.7 hours. Groups II and III showed decreased (not significant) clearance of ethinyl estradiol. Tobacco use had no effect on steroid pharmacokinetics in the non-OC users. Although chronic OC use did not affect ethinyl estradiol clearance, a joint effect of tobacco/OC use on enhancing clearance of ethinyl estradiol appeared to occur. A linear relationship was found between 24-hour trough serum concentrations and AUC values of both steroids that may facilitate population monitoring studies of OC exposure.

Previous studies suggested that in patients with affective illness, lithium ion accumulated more in erythrocytes (higher erythrocyte lithium ratio) as well as in the total body (greater lithium retention). The aim of this study was to estimate the relationship between erythrocyte lithium transport mechanisms and the parameters of lithium pharmacokinetics in 11 affective patients during depressive episodes. It was found that the activity of erythrocyte lithium-sodium countertransport (LSC) governing lithium transport out of the erythrocytes, measured in vitro, significantly correlated with rate constant (K21) of lithium transport from intra-to extracellular compartment. Passive lithium diffusion (PLD) in erythrocytes correlated with K21/ K12 ratio. Neither LSC nor PLD correlated with renal lithium clearance. The results show that, in affective patients, the activity of erythrocyte LSC may serve as a model of the intensity of lithium extrusion from cells in the total body.KEY WORDS-Lithium pharmockinetics, erythrocyte lithium-sodium countertransport, affective illness.

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