Physiologie and temporal variation in hepatic elimination of midazolam

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Abstract
Midazolam [a hypnotic benzodiazepine] kinetics were evaluated in 6 healthy male subjects after single oral (15 mg) and i.v. (0.075 mg/kg) doses. The 3-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). 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 (37-44%). Evidently, posture and circadian rhythm are important variables affecting blood flow-dependent hepatic elimination of midazolam.

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