Physiologie 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 processes 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. Clinical Pharmacology and Therapeutics (1982) 32, 107–112; doi: 10.1038/clpt.1982.133