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In Vitro Assessment of Drug-drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters.
MedLine Citation:
PMID:  23293300     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
In this paper, the inhibitory effect of boceprevir (BOC), an inhibitor of hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease, was evaluated in vitro against a panel of drug metabolizing enzymes and transporters. BOC, a known substrate for cytochrome P450 (CYP) 3A and aldo-ketoreductases, was a reversible time-dependent inhibitor (k(inact) = 0.12 min(-1), K(I) = 6.1 μM) of CYP3A4/5, but not an inhibitor of other major CYPs, nor of UDP-glucuronosyltransferases (UGT) 1A1 and 2B7. BOC showed weak to no inhibition of breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), and multidrug resistance protein 2 (MRP2). It was a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B1 and -1B3, with an IC(50) of 18 and 4.9 μM, respectively. In human hepatocytes, BOC inhibited CYP3A-mediated metabolism of midazolam, OATP1B-mediated hepatic uptake of pitavastatin, and both the uptake and metabolism of atorvastatin. The inhibitory potency of BOC was lower than known inhibitors of CYP3A (ketoconazole), OATP1B (rifampin), or both (telaprevir). BOC was a substrate for Pgp and BCRP, but not for OATP1B1, -1B3, -2B1, organic cation transporter (OCT1), or sodium/taurocholate co-transporting peptide. Overall, our data suggest that BOC has potential to cause pharmacokinetic interactions via inhibition of CYP3A and CYP3A/OATP1B interplay, with the interaction magnitude lower than those observed with known potent inhibitors. Conversely, pharmacokinetic interactions of BOC, either as a perpetrator or victim, via other major CYPs and transporters tested are less likely of clinical significance. The results from clinical drug-drug interaction studies conducted thus far are generally supportive of these conclusions.
Authors:
Xiaoyan Chu; Xiaoxin Cai; Donghui Cui; Cuyue Tang; Anima Ghosal; Grace Hoyee Chan; Mitchell D Green; Yuhsin Kuo; Yuexia Liang; Cheri M Maciolek; Jairam Palamanda; Raymond Evers; Thomayant Prueksaritanont
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-4
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  -     ISSN:  1521-009X     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-7     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Merck Sharp & Dohme Corp.
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