当前位置： SCI文献检索 > ANTIMICROBIAL AGENTS AND CHEMOTHERAPY期刊下所有文献 > Metabolism and pharmacokinetics of the anti-hepatitis C virus nucleotide prodrug GS-6620.

Metabolism and pharmacokinetics of the anti-hepatitis C virus nucleotide prodrug GS-6620.

Abstract：

:The anti-hepatitis C virus nucleotide prodrug GS-6620 employs a double-prodrug approach, with l-alanine-isopropyl ester and phenol moieties attached to the 5'-phosphate that release the nucleoside monophosphate in hepatocytes and a 3'-isobutyryl ester added to improve permeability and oral bioavailability. Consistent with the stability found in intestinal homogenates, following oral administration, intact prodrug levels in blood plasma were the highest in dogs, followed by monkeys, and then were the lowest in hamsters. In contrast, liver levels of the triphosphate metabolite at the equivalent surface area-adjusted doses were highest in hamsters, followed by in dogs and monkeys. Studies in isolated primary hepatocytes suggest that relatively poor oral absorption in hamsters and monkeys was compensated for by relatively efficient hepatocyte activation. As intestinal absorption was found to be critical to the effectiveness of GS-6620 in nonclinical species, stomach pH, formulation, and food effect studies were completed in dogs. Consistent with in vitro absorption studies in Caco-2 cells, the absorption of GS-6620 was found to be complex and highly dependent on concentration. Higher rates of metabolism were observed at lower concentrations that were unable to saturate intestinal efflux transporters. In first-in-human clinical trials, the oral administration of GS-6620 resulted in poor plasma exposure relative to that observed in dogs and in large pharmacokinetic and pharmacodynamic variabilities. While a double-prodrug approach, including a 3'-isobutyryl ester, provided higher intrinsic intestinal permeability, this substitution appeared to be a metabolic liability, resulting in extensive intestinal metabolism and relatively poor oral absorption in humans.

journal_name

Antimicrob Agents Chemother

journal_title

Antimicrobial agents and chemotherapy

authors

Murakami E,Wang T,Babusis D,Lepist EI,Sauer D,Park Y,Vela JE,Shih R,Birkus G,Stefanidis D,Kim CU,Cho A,Ray AS

doi

10.1128/AAC.02350-13

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

1943-51

issue

eissn

0066-4804

issn

1098-6596

pii

AAC.02350-13

journal_volume

pub_type

杂志文章

在线工具

Metabolism and pharmacokinetics of the anti-hepatitis C virus nucleotide prodrug GS-6620.