@entity4914 is a major determinant of XXXX metabolism in vivo: effects of liver function.

@entity1 @entity82 @entity73 @entity409 @entity3755 @entity17542 @entity26273 @entity3303 @entity1575 @entity4914
OBJECTIVES: This study was designed (1) to evaluate the effect of a @entity4914 inhibitor, @entity3755 , on the pharmacokinetics of intravenous @entity3303 and its 2 pharmacologically active metabolites, @entity17542 ( @entity17542 ) and @entity26273 (GX), to confirm recent in vitro results indicating that @entity4914 is the main isoform responsible for @entity3303 biotransformation and (2) to assess whether liver function has any influence on the @entity3755 - @entity3303 interaction. METHODS: The study was carried out in 10 healthy volunteers and 20 @entity1 with @entity82 , 10 with mild ( @entity1 grade A) and 10 with severe ( @entity1 grade C) @entity409 , according to a randomized, double-blind, 2-phase, crossover design. In one phase all @entity1 received placebo for 6 days; in the other phase they received 50 mg @entity3755 for 2 days and 100 mg @entity3755 for the next 4 days. On day 6, a 1-mg/kg @entity3303 dose was administered intravenously 2 hours after the last dose of @entity3755 or placebo. Plasma concentrations of @entity3303 , @entity17542 , GX, and @entity3755 were measured up to 12 hours after @entity3303 injection. RESULTS: The effects of @entity3755 coadministration were dependent on liver function. @entity3303 clearance was decreased on average by 60% (from 12.1 mL/min.kg to 4.85 mL/min.kg, P <.001) in healthy subjects and by 44% (from 9.83 mL/min.kg to 5.06 mL/min.kg, P <.001) in @entity1 with mild @entity409 , with proportional increases in terminal half-lives, whereas virtually no effect was produced in @entity1 with severe @entity409 (4.21 mL/min.kg versus 3.65 mL/min.kg, P >.05). Analogous effects were observed on @entity17542 and GX formation kinetics, which were @entity73 in healthy subjects and @entity1 with mild @entity1575 but virtually unaffected in @entity1 with severe @entity82 . CONCLUSION: @entity4914 is the enzyme principally responsible for the metabolic disposition of @entity3303 in subjects with normal liver function. The extent of @entity3755 - @entity3303 interaction decreases as liver function worsens, most likely because of the concomitant decrease in the hepatic level of @entity4914 . These observations indicate that results obtained in healthy subjects cannot be extended a priori to @entity1 with @entity409 , but the clinical consequences of inhibition of drug metabolism must also be assessed in such @entity1 .
