title: Different interaction profiles of direct-acting anti-hepatitis C virus agents with human organic anion transporting polypeptides.
abstract: Simeprevir (SMV), asunaprevir (ASV), daclatasvir (DCV), and sofosbuvir (SFV), which are newly developed direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) infection, are among the key components of anti-HCV regimens. Preclinical studies have identified inhibitory properties for some of these DAAs against organic anion transporting polypeptide 1B (OATP1B) functions. However, their details remain mostly uncharacterized. Because OATP1B1 and OATP1B3 play determinant roles in the pharmacokinetics of various drugs via their uptake into human hepatocytes, it is plausible that the inhibition of these OATP1Bs by a DAA would create a potential risk of drug-drug interaction, which has been an emerging concern in anti-HCV therapy. Accordingly, in the present study, we intended to clarify the inhibitory characteristics of newly developed DAAs toward OATP1B1 and -1B3 functions. The results of our coincubation inhibition assays have shown that all tested DAAs could inhibit OATP1B1 functions and that SMV, ASV, and DCV (to a lesser extent), but not SFV, exhibited long-lasting preincubation inhibitory effects on OATP1B1 functions. It was also found that the preincubation inhibitory effects of SMV and ASV could augment their coincubation inhibition potency. Furthermore, significant, but differential, inhibitory effects of the DAAs on the OATP1B3 function were identified. To summarize, our results clearly show that the newly developed DAAs are newly identified OATP1B1 and OATP1B3 inhibitors with distinctive interaction properties. It is believed that these inhibition profiles will provide essential information to all concerned parties with respect to the clinical significance of DAA-mediated inhibition of OATP1Bs in anti-HCV therapy.
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba-shi, Chiba, Japan tomomif@faculty.chiba-u.jp.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Furihata
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba-shi, Chiba, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba-shi, Chiba, Japan.
authors.forename: Zhongguo
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Institute of Clinical Medicine and Research, Jikei University School of Medicine, Kashiwa-shi, Chiba, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Tsubota
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba-shi, Chiba, Japan.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba-shi, Chiba, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba-shi, Chiba, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba-shi, Chiba, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Chiba
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002219:Carbamates; D015870:Gene Expression; D057809:HEK293 Cells; D016174:Hepacivirus; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011759:Pyrrolidines; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000069616:Simeprevir; D000069474:Sofosbuvir; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; D007546:Isoquinolines; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011759:Pyrrolidines; D011994:Recombinant Proteins; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides; D000069616:Simeprevir; D014542:Uridine Monophosphate; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir; D000069474:Sofosbuvir