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In vitro assessment of drug-drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters.
Drug Metab Dispos. 2013 Mar; 41(3):668-81.DM

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+Show Affiliations

Merck Sharp & Dohme Corporation, Whitehouse Station, New Jersey, USA. xiaoyan_chu@merck.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23293300

Citation

Chu, Xiaoyan, et al. "In Vitro Assessment of Drug-drug Interaction Potential of Boceprevir Associated With Drug Metabolizing Enzymes and Transporters." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 41, no. 3, 2013, pp. 668-81.
Chu X, Cai X, Cui D, et al. In vitro assessment of drug-drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters. Drug Metab Dispos. 2013;41(3):668-81.
Chu, X., Cai, X., Cui, D., Tang, C., Ghosal, A., Chan, G., Green, M. D., Kuo, Y., Liang, Y., Maciolek, C. M., Palamanda, J., Evers, R., & Prueksaritanont, T. (2013). In vitro assessment of drug-drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 41(3), 668-81. https://doi.org/10.1124/dmd.112.049668
Chu X, et al. In Vitro Assessment of Drug-drug Interaction Potential of Boceprevir Associated With Drug Metabolizing Enzymes and Transporters. Drug Metab Dispos. 2013;41(3):668-81. PubMed PMID: 23293300.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro assessment of drug-drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters. AU - Chu,Xiaoyan, AU - Cai,Xiaoxin, AU - Cui,Donghui, AU - Tang,Cuyue, AU - Ghosal,Anima, AU - Chan,Grace, AU - Green,Mitchell D, AU - Kuo,Yuhsin, AU - Liang,Yuexia, AU - Maciolek,Cheri M, AU - Palamanda,Jairam, AU - Evers,Raymond, AU - Prueksaritanont,Thomayant, Y1 - 2013/01/04/ PY - 2013/1/8/entrez PY - 2013/1/8/pubmed PY - 2013/7/16/medline SP - 668 EP - 81 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 41 IS - 3 N2 - 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. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/23293300/In_vitro_assessment_of_drug_drug_interaction_potential_of_boceprevir_associated_with_drug_metabolizing_enzymes_and_transporters_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=23293300 DB - PRIME DP - Unbound Medicine ER -