INDUCTION OF THEOPHYLLINE CLEARANCE BY RIFAMPIN AND RIFABUTIN IN HEALTHY MALE-VOLUNTEERS

Rifampin and rifabutin induce the metabolism of many drugs, which may result in subtherapeutic concentrations and failure of therapy, Howeve r, differences between rifabutin and rifampin in potency of induction, and the specific enzymes which are altered, are not clear. This study , involving 12 adult male volunteers, compared the effects of 14-day c ourses of rifampin and rifabutin on clearance of theophylline, a subst rate for the hepatic microsomal enzyme CYP1A2, Subjects were given ora l theophylline solution (5 mg/kg of body weight) on day 1 and then ran domized to receive daily rifampin (300 mg) or rifabutin (300 mg) on da ys 3 to 16, Theophylline was readministered as described above on day 15, The first treatment sequence was followed by a 2-week washout peri od; subjects then received the alternative treatment, Theophylline con centrations were determined for 46 h after each dose, and pharmacokine tic parameters were determined, One subject developed flu-like symptom s while taking rifabutin and withdrew voluntarily, Results from the re maining 11 subjects are reported, Compared with the baseline, the mean area under the concentration-time curve (AUG) (+/- standard deviation ) for theophylline declined significantly following rifampin treatment (from 140 +/- 37 to 100 +/- 24 mu g . h/ml, P < 0.001); there was no significant change following rifabutin treatment (136 +/- 48 to 128 +/ - 45 mu g . h/ml), Baseline theophylline AUCs before each treatment ph ase were not different, A comparison of equal doses of rifampin and ri fabutin administered to healthy volunteers for 2 weeks indicates that induction of CYP1A2, as measured by theophylline clearance, is signifi cantly less following rifabutin treatment than it is following rifampi n treatment, However, the relative induction potency for other metabol ic enzymes remains to be investigated.