title: Multiple-dose lorazepam kinetics: shuttling of lorazepam glucuronide between the circulation and the gut during day- and night-time dosing intervals in response to feeding.
abstract: Lorazepam kinetics were examined in seven healthy males age 18 to 30 years after single- and multiple-dose lorazepam administration and in the presence and absence of neomycin and cholestyramine to block the enterohepatic circulation of the drug. Methods used a simultaneous i.v./p.o. dosing regimen with provision to measure lorazepam clearance during day- and night-time dosing intervals. The day-time steady-state clearance of free lorazepam measured 7.55 +/- 1.95 ml/min/kg (mean +/- S.D.) and was identical to that observed after single-dose administration (7.68 +/- 3.19 ml/min/kg). Neomycin and cholestyramine increased lorazepam clearances 5 to 45% (P < or = .05) as would be expected for interruption of an enterohepatic circulation and in keeping with previous observations under nonsteady-state conditions. Lorazepam clearances were the same during the day as during the night, except in the presence of neomycin and cholestyramine, where night-time clearances were significantly greater (10.16 +/- 3.52 vs. 8.77 +/- 2.43 ml/min/kg, P < or = .05). Urinary recoveries of lorazepam glucuronide, on the other hand, were greater during the day than during the night (114 +/- 11 vs. 77 +/- 15%, P < or = .05) and in all cases were greater than 100% of the administered dose for that interval. Thus, there is a diurnal variation in lorazepam elimination consistent with a fasting-induced increase in hepatic glucuronidation during the night. This, combined with the relative inactivity of the gut during this period, serves to trap the glucuronide and delay its transfer back to the systemic circulation and urine.
authors.affiliation: Department of Medicine, University of Saskatchewan, Saskatoon, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Chaudhary
authors.forename: R A
authors.initials: RA
authors.lastname: Lane
authors.forename: D
authors.initials: D
authors.lastname: Woo
authors.forename: R J
authors.initials: RJ
authors.lastname: Herman
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002940:Circadian Rhythm / Q000502:physiology*; D004334:Drug Administration Schedule; D004435:Eating / Q000502:physiology*; D004764:Enterohepatic Circulation / Q000502:physiology*; D005965:Glucuronates / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism*; D008140:Lorazepam / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male
chemical_list: D005965:Glucuronates; D008140:Lorazepam