Physiologic and temporal variation in hepatic elimination of midazolam

Midazolam kinetics were evaluated in six healthy male subjects after single oral (15 mg)and intravenous (0.075 mg/kg) doses. The three-part randomized crossover study consisted of a morning dose in supine position (part A) and morning (part B) and evening (part C) doses under ambulant (sitting/walking) conditions. While no significant changes could be observed in the absorption and distribution process or the elimination half lives, total plasma clearance was higher during part A (616+/-157 ml/min, P=0.01) and C(463+/-82 ml/min, P=0.02), than in part B (317+/-110 ml/min, +/-SD). Since the intrinsic (oral) clearance was also higher during part A (1656+/-657 ml/min, P=0.003) and C(1310+/-579 ml/min, P=0.024) than during part B(710+/-241 ml/min), bioavailability did not change (range 37 to 44%). These data indicate that posture and circadian rhythm are important variables affecting blood flow-dependent hepatic elimination of midazolam.