Disposition of lorazepam in Gilbert's syndrome: effects of fasting, feeding, and enterohepatic circulation.

Abstract

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.