Preclinical pharmacokinetics and metabolism of a potent non-nucleoside inhibitor of the hepatitis C virus NS5B polymerase.
The disposition of compound A, a potent inhibitor of the hepatitis C virus (HCV) NS5B polymerase, was characterized in animals in support of its selection for further development. Compound A exhibited marked species differences in pharmacokinetics. Plasma clearance was 44 ml min-1 kg-1 in rats, 9 ml min-1 kg-1 in dogs and 16 ml min-1 kg-1 in rhesus monkeys. Oral bioavailability was low in rats (10%) but significantly higher in dogs (52%) and monkeys (26%). Compound A was eliminated primarily by metabolism in rats, with biliary excretion accounting for 30% of its clearance. Metabolism was mainly mediated by cyclohexyl hydroxylation, with N-deethylation and acyl glucuronide formation constituting minor metabolic pathways. Qualitatively, the same metabolites were identified using in vitro systems from all species studied, including humans. The low oral bioavailability of compound A in rats was mostly due to poor intestinal absorption. This conclusion was borne out by the findings that hepatic extraction in the rat was only 30%, intraperitoneal bioavailability was good, and compound A was poorly absorbed from the rat isolated intestinal loop, with no detectable intestinal metabolism. Compound A was not an inhibitor of major human cytochrome P450 enzymes, indicating minimal potential for clinical drug-drug interactions. The metabolic clearance of compound A in rat, dog and monkey hepatocytes correlated with the systemic clearance observed in these species. Since compound A was very stable in human hepatocytes, the results suggest that it will be a low clearance drug in humans.
Giuliano
C
C
Department of Pharmacology, Istituto di Ricerche di Biologia Molecolare (IRBM) P. Angeletti, Merck Research Laboratories Rome, Pomezia, Italy.
Fiore
F
F
Di Marco
A
A
Padron Velazquez
J
J
Bishop
A
A
Bonelli
F
F
Gonzalez-Paz
O
O
Marcucci
I
I
Harper
S
S
Narjes
F
F
Pacini
B
B
Monteagudo
E
E
Migliaccio
G
G
Rowley
M
M
Laufer
R
R
D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism*; D009705:Nucleosides / Q000493:pharmacokinetics; D009928:Organ Specificity; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase
D004791:Enzyme Inhibitors; D007211:Indoles; D009705:Nucleosides; D010880:Piperidines; D000644:Quaternary Ammonium Compounds; D017361:Viral Nonstructural Proteins; C507934:(1-((6-carboxy-2-(4-chlorophenyl)-3-cyclohexyl-1H-indol-1-yl))acetyl)-N,N-diethylpiperidine-4-aminium chloride; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase