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Disposition of Lorazepam in Gilbert's Syndrome: Effects of Fasting, Feeding, and Enterohepatic Circulation
Author(s) -
Herman Robert J.,
Chaudhary Archana,
Szakacs Cameron B.
Publication year - 1994
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1994.tb01969.x
Subject(s) - enterohepatic circulation , lorazepam , glucuronidation , medicine , endocrinology , dosing , cholestyramine , metabolism , chemistry , anesthesia , cholesterol , biochemistry , enzyme , microsome
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.