PMID- 34311070 OWN - NLM STAT- MEDLINE DCOM- 20210812 LR - 20240425 IS - 1879-0720 (Electronic) IS - 0928-0987 (Print) IS - 0928-0987 (Linking) VI - 165 DP - 2021 Oct 1 TI - Pre-incubation with OATP1B1 and OATP1B3 inhibitors potentiates inhibitory effects in physiologically relevant sandwich-cultured primary human hepatocytes. PG - 105951 LID - S0928-0987(21)00254-2 [pii] LID - 10.1016/j.ejps.2021.105951 [doi] AB - Organic anion transporting polypeptides (OATP)1B1 and OATP1B3 are liver-specific transport proteins that express on the basolateral membrane of human hepatocytes and mediate hepatic uptake of many drugs, including statins. They are important determinants of transporter-mediated drug-drug interactions (DDIs). It has been reported that pre-incubation with some OATP1B1 and OATP1B3 inhibitors potentiates the inhibitory effects, yielding reduced IC(50) values. The US FDA draft guidance has recently recommended to use the lower IC(50) values after inhibitor-preincubation to assess OATP1B1 and OATP1B3-mediated DDIs. However, it remains unknown whether the potentiation effects of inhibitor-preincubation on IC(50) values occur in a physiologically relevant cell model. The current study was designed to determine the IC(50) values of OATP1B1 and OATP1B3 inhibitors everolimus (EVR), sirolimus (SIR), and dasatinib against OATP1B substrates in physiologically relevant primary human hepatocytes with or without inhibitor-preincubation and to compare the OATP-mediated DDI prediction using data from primary human hepatocytes and that reported previously in transporter-expressing cell lines. Primary human hepatocytes were cultured in a sandwich configuration. Accumulation of [(3)H]-CCK-8 (1 microM, 1.5 min), [(3)H]-rosuvastatin (0.5 microM, 2 min) and [(3)H]-pitavastatin (1 microM, 0.5 min) was determined in human sandwich-cultured hepatocytes (SCH) in the presence of vehicle control or an inhibitor with or without inhibitor-preincubation at designated concentrations, and was utilized to determine the IC(50) values for these inhibitors. R-value models were used to predict OATP-mediated DDIs. Pre-incubation with EVR at a clinically relevant concentration of 0.2 microM significantly reduced accumulation of [(3)H]-CCK-8 and [(3)H]-rosuvastatin even after washing. Reduced IC(50) values following inhibitor pre-incubation were observed for all three inhibitors using [(3)H]-CCK-8 and [(3)H]-rosuvastatin as substrates in human SCH. The IC(50) values after inhibitor-preincubation were lower or comparable in transporter-expressing cell lines compared with that in human SCH. For dasatinib, R-values from both cell lines and human SCH were greater than the US FDA cut-off value of 1.1. For EVR, R values from cell lines were 1.23 and were lowered to near 1.1 (1.08-1.09) in human SCH. For SIR, R values from either cell type were less than the cut-off values of 1.1. In conclusion, the current study is the first to report that pre-incubation with OATP1B inhibitors potentiates inhibitory effects in physiologically relevant primary human hepatocytes, supporting the rationale of the current US FDA draft guidance of including an inhibitor-preincubation step when assessing OATP-mediated DDIs in vitro. IC(50) values after inhibitor-preincubation in transporter-expressing cell lines may be used for DDI prediction for the purpose of mitigating false-negative OATP-mediated DDI prediction. CI - Copyright (c) 2021 Elsevier B.V. All rights reserved. FAU - Farasyn, Taleah AU - Farasyn T AD - Department of Pharmaceutical Sciences, US. FAU - Pahwa, Sonia AU - Pahwa S AD - Department of Pharmaceutical Sciences, US. FAU - Xu, Chao AU - Xu C AD - Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK US. FAU - Yue, Wei AU - Yue W AD - Department of Pharmaceutical Sciences, US. Electronic address: wei-yue@ouhsc.edu. LA - eng GR - P30 CA225520/CA/NCI NIH HHS/United States GR - R01 GM094268/GM/NIGMS NIH HHS/United States PT - Journal Article DEP - 20210724 PL - Netherlands TA - Eur J Pharm Sci JT - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JID - 9317982 RN - 0 (Liver-Specific Organic Anion Transporter 1) RN - 0 (Organic Anion Transporters) RN - 0 (Organic Anion Transporters, Sodium-Independent) RN - 0 (Solute Carrier Organic Anion Transporter Family Member 1B3) SB - IM MH - Biological Transport MH - Drug Interactions MH - HEK293 Cells MH - *Hepatocytes/metabolism MH - Humans MH - Liver-Specific Organic Anion Transporter 1/metabolism MH - *Organic Anion Transporters/metabolism MH - Organic Anion Transporters, Sodium-Independent/metabolism MH - Solute Carrier Organic Anion Transporter Family Member 1B3/metabolism PMC - PMC11005446 MID - NIHMS1973893 OTO - NOTNLM OT - Drug interactions OT - Drug transport OT - Hepatic transport OT - Hepatocytes OT - Organic anion-transporting polypeptide OT - Pharmacokinetics OT - Physiologically based pharmacokinetic modeling OT - Transporters EDAT- 2021/07/27 06:00 MHDA- 2021/08/13 06:00 PMCR- 2024/04/10 CRDT- 2021/07/26 20:12 PHST- 2021/03/30 00:00 [received] PHST- 2021/06/11 00:00 [revised] PHST- 2021/07/08 00:00 [accepted] PHST- 2021/07/27 06:00 [pubmed] PHST- 2021/08/13 06:00 [medline] PHST- 2021/07/26 20:12 [entrez] PHST- 2024/04/10 00:00 [pmc-release] AID - S0928-0987(21)00254-2 [pii] AID - 10.1016/j.ejps.2021.105951 [doi] PST - ppublish SO - Eur J Pharm Sci. 2021 Oct 1;165:105951. doi: 10.1016/j.ejps.2021.105951. Epub 2021 Jul 24.