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Disposition of lorazepam in human beings: Enterohepatic recirculation and first‐pass effect
Author(s) -
Herman Robert J,
Van Pham J Duc,
Szakacs Cameron B N
Publication year - 1989
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1989.101
Subject(s) - enterohepatic circulation , lorazepam , pharmacokinetics , cholestyramine , pharmacology , disposition , bioavailability , oral administration , clinical pharmacology , chemistry , drug , glucuronide , medicine , metabolism , anesthesia , cholesterol , psychology , social psychology
The effects of neomycin and cholestyramine on the disposition of lorazepam was examined in seven healthy drug‐free men. Half‐life as determined for the oral route was, in all subjects, 15% to 35% less than that determined for the intravenous route. Free oral clearance was slightly but not significantly less than free systemic clearance, but the ratio of the AUC of lorazepam glucuronide corrected for dose was twofold greater by the oral route. Urinary recoveries also differed (71.6% and 50.4%, oral versus intravenous). Neomycin and cholestyramine treatment resulted in a 19% to 26% reduction in half‐life attendant on a 34% increase in free oral clearance and a 24% increase in free systemic clearance. This suggests that lorazepam undergoes significant enterohepatic recirculation in human beings and that there exists an extrahepatic pathway, at least for the intravenous route. Since pharmacokinetic measurements do not take these physiologic processes into account, the drug cannot properly be used as a marker of conjugative metabolism. Clinical Pharmacology and Therapeutics (1989) 46, 18–25; doi: 10.1038/clpt.1989.101