Substrate-dependent inhibition of organic anion transporting polypeptide 1B1: comparative analysis with prototypical probe substrates estradiol-17β-glucuronide, estrone-3-sulfate, and sulfobromophthalein.
Organic anion transporting polypeptide (OATP) 1B1 plays an important role in the hepatic uptake of many drugs, and the evaluation of OATP1B1-mediated drug-drug interactions (DDIs) is emphasized in the latest DDI (draft) guidance documents from U.S. and E.U. regulatory agencies. It has been suggested that some OATP1B1 inhibitors show a discrepancy in their inhibitory potential, depending on the substrates used in the cell-based assay. In this study, inhibitory effects of 14 compounds on the OATP1B1-mediated uptake of the prototypical substrates [³H]estradiol-17β-glucuronide (E₂G), [³H]estrone-3-sulfate (E₁S), and [³H]sulfobromophthalein (BSP) were studied in OATP1B1-transfected cells. Inhibitory potencies of tested compounds varied depending on the substrates. Ritonavir, gemfibrozil, and erythromycin caused remarkable substrate-dependent inhibition with up to 117-, 14-, and 13-fold difference in their IC₅₀ values, respectively. Also, the clinically relevant OATP inhibitors rifampin and cyclosporin A exhibited up to 12- and 6-fold variation in their IC₅₀ values, respectively. Regardless of the inhibitors tested, the most potent OATP1B1 inhibition was observed when [³H]E₂G was used as a substrate. Mutual inhibition studies of OATP1B1 indicated that E₂G and E₁S competitively inhibited each other, whereas BSP noncompetitively inhibited E₂G uptake. In addition, BSP inhibited E₁S in a competitive manner, but E₁S caused an atypical kinetics on BSP uptake. This study showed substrate-dependent inhibition of OATP1B1 and demonstrated that E₂G was the most sensitive in vitro OATP1B1 probe substrate among three substrates tested. This will give us an insight into the assessment of clinically relevant OATP1B1-mediated DDI in vitro with minimum potential of false-negative prediction.
Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co., Ltd., Tokodai, Tsukuba-shi, Ibaraki, Japan (S.I., Y.N., T.K., O.T., K.K., T.Y.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama-shi, Kanagawa, Japan (Y.S.).
Saki
S
Izumi
Yoshitane
Y
Nozaki
Takafumi
T
Komori
Kazuya
K
Maeda
Osamu
O
Takenaka
Kazutomi
K
Kusano
Tsutomu
T
Yoshimura
Hiroyuki
H
Kusuhara
Yuichi
Y
Sugiyama
D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism; D004970:Estrone / Q000031:analogs & derivatives* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013448:Sulfobromophthalein / Q000378:metabolism*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D013448:Sulfobromophthalein; C025483:estradiol-17 beta-glucuronide; D004970:Estrone; D004958:Estradiol; C017296:estrone sulfate