title: In vitro assessment of drug-drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters.
abstract: The inhibitory effect of boceprevir (BOC), an inhibitor of hepatitis C virus nonstructural protein 3 protease was evaluated in vitro against a panel of drug-metabolizing enzymes and transporters. BOC, a known substrate for cytochrome P450 (P450) CYP3A and aldo-ketoreductases, was a reversible time-dependent inhibitor (k(inact) = 0.12 minute(-1), K(I) = 6.1 µM) of CYP3A4/5 but not an inhibitor of other major P450s, nor of UDP-glucuronosyltransferases 1A1 and 2B7. BOC showed weak to no inhibition of breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or multidrug resistance protein 2. 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, OATP1B3, OATP2B1, organic cation transporter, or sodium/taurocholate cotransporting peptide. Overall, our data suggest that BOC has the 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 P450s and transporters tested are less likely to be of clinical significance. The results from clinical drug-drug interaction studies conducted thus far are generally supportive of these conclusions.
authors.affiliation: Merck Sharp & Dohme Corporation, Whitehouse Station, New Jersey, USA. xiaoyan_chu@merck.com
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chu
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Cai
authors.forename: Donghui
authors.initials: D
authors.lastname: Cui
authors.forename: Cuyue
authors.initials: C
authors.lastname: Tang
authors.forename: Anima
authors.initials: A
authors.lastname: Ghosal
authors.forename: Grace
authors.initials: G
authors.lastname: Chan
authors.forename: Mitchell D
authors.initials: MD
authors.lastname: Green
authors.forename: Yuhsin
authors.initials: Y
authors.lastname: Kuo
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Liang
authors.forename: Cheri M
authors.initials: CM
authors.lastname: Maciolek
authors.forename: Jairam
authors.initials: J
authors.lastname: Palamanda
authors.forename: Raymond
authors.initials: R
authors.lastname: Evers
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000633:toxicity; D001711:Biotransformation; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000633:toxicity; D004798:Enzymes / Q000235:genetics / Q000378:metabolism*; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D018374:LLC-PK1 Cells; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D027381:Liver-Specific Organic Anion Transporter 1; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D049990:Membrane Transport Modulators / Q000378:metabolism* / Q000633:toxicity; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D011994:Recombinant Proteins / Q000378:metabolism; D013552:Swine; D014162:Transfection
chemical_list: D000998:Antiviral Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D004798:Enzymes; D027381:Liver-Specific Organic Anion Transporter 1; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D011994:Recombinant Proteins; C503999:SLCO1B1 protein, human; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; D010088:Oxidoreductases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D014453:Glucuronosyltransferase