IMPAIRMENT OF CAFFEINE CLEARANCE BY CHRONIC USE OF LOW-DOSE ESTROGEN-CONTAINING ORAL-CONTRACEPTIVES

The effect of chronic (> 3 mo.) administration of low-dose estrogen-containing (< 50 .mu.g estrogen) oral contraceptives (OCS) on the pharmacokinetics of caffeine was examined in a treated females matched with 9 non-smoking, drug-free, healthy control females of similar age, weight and ethnic origin. Each subject received 162 mg caffeine base orally after an overnight fast. OCS subjects had a prolonged elimination half-life of caffeine, (mean 7.88 h vs. 5.37 h in the controls). This was the result of marked impairment of the plasma clearance of caffeine (1.05 vs. 1.75 ml/min per kg, respectively), with no change in apparent volume of distribution (0.685 in OCS vs. 0.750 l/kg in the control group). The absorption parameters determined were peak plasma caffeine concentration (3.99 vs. 4.09 .mu.g/ml) and time to peak concentration after drug administration (1.52 vs. 0.79), which was moderately prolonged in OCS users. Thus, caffeine clearance, previously reported to be a specific marker of cytochrome P-448 activity in man, is decreased by chronic OCS use. OCS may cause significant impairment of this enzyme activity as assessed in vivo. With chronic caffeine consumption, OCS users are predicted to have an increased steady-state plasma caffeine concentration as compared to non-OCS users.