Disposition of lorazepam in Gilbert's syndrome: effects of fasting, feeding, and enterohepatic circulation.
The effects of fasting and feeding of a high-carbohydrate, low-fat diet on the glucuronidation and enterohepatic circulation (EHC) of lorazepam were examined in seven healthy men (age 18-30 years) and seven matched patients with Gilbert's syndrome. A simultaneous intravenous/oral dosing regimen was used, with half of each group receiving treatment with neomycin and cholestyramine (neo/chol) to block the EHC of the drug. Feeding increased the clearance of free lorazepam from 10.96 +/- 0.56 (mean +/- SD) to 14.11 +/- 1.21 mL/min/kg (P = 0.05) in patients with Gilbert's syndrome when examined in the presence of neo/chol. Clearances, on the other hand, decreased with feeding in control Gilbert's patients (7.61 +/- 0.54 versus 8.82 +/- 0.48 mL/min/kg), although the differences were not significant (P = 0.09). In contrast to both of these groups, feeding decreased lorazepam clearances (13.33 +/- 0.32 to 12.45 +/- 0.52 mL/min/kg, P = 0.17) in neo/chol-treated normals and increased clearances (9.95 +/- 1.84 to 12.38 +/- 2.05 mL/min/kg, P = 0.04) in control normals. Lorazepam clearances were also 20-40% lower in patients with Gilbert's syndrome compared with normals when studied fasting and with neo/chol, or fed and in the control state (P < 0.05 for both). Thus, the glucuronidation and EHC of lorazepam is sensitive both to diet and to the presence or absence of the Gilbert's trait.
Department of Medicine, University of Saskatchewan, Saskatoon, Canada.
R J
RJ
Herman
A
A
Chaudhary
C B
CB
Szakacs
D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D002792:Cholestyramine Resin / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D018752:Diet, Fat-Restricted; D004347:Drug Interactions; D004764:Enterohepatic Circulation / Q000187:drug effects / Q000502:physiology*; D005215:Fasting / Q000378:metabolism*; D018565:Food-Drug Interactions; D005878:Gilbert Disease / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D008140:Lorazepam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D009355:Neomycin / Q000494:pharmacology
D005965:Glucuronates; D002792:Cholestyramine Resin; D009355:Neomycin; D008140:Lorazepam