Substrate-dependent drug-drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3.
Hepatic uptake carriers of the organic anion-transporting peptide (OATP) family of solute carriers are more and more recognized as being involved in hepatic elimination of many drugs and potentially associated drug-drug interactions. The gemfibrozil-statin interaction was studied at the level of active hepatic uptake as a model for such drug-drug interactions. Active, temperature-dependent uptake of fluvastatin into primary human hepatocytes was shown. Multiple transporters are involved in this uptake as Chinese hamster ovary or HEK293 cells expressing either OATP1B1 (K(m) = 1.4-3.5 microM), OATP2B1 (K(m) = 0.7-0.8 microM), or OATP1B3 showed significant fluvastatin uptake relative to control cells. For OATP1B1 the inhibition by gemfibrozil was substrate-dependent as the transport of fluvastatin (IC(50) of 63 microM), pravastatin, simvastatin, and taurocholate was inhibited by gemfibrozil, whereas the transport of estrone-3-sulfate and troglitazone sulfate (both used at 3 microM) was not affected. The OATP1B1- but not OATP2B1-mediated transport of estrone-3-sulfate displayed biphasic saturation kinetics, with two distinct affinity components for estrone-3-sulfate (0.23 and 45 microM). Only the high-affinity component was inhibited by gemfibrozil. Recombinant OATP1B1-, OATP2B1-, and OATP1B3-mediated fluvastatin transport was inhibited to 97, 70, and 62% by gemfibrozil (200 microM), respectively, whereas only a small inhibitory effect by gemfibrozil (200 microM) on fluvastatin uptake into primary human hepatocytes was observed (27% inhibition). The results indicate that the in vitro engineered systems can not always predict the behavior in more complex systems such as freshly isolated primary hepatocytes. Therefore, selection of substrate, substrate concentration, and in vitro transport system are critical for the conduct of in vitro interaction studies involving individual liver OATP carriers.
Noé
Johannes
J
F. Hoffmann-La Roche Ltd., Non-Clinical Development-Drug Safety, Basel, Switzerland.
Portmann
Renée
R
Brun
Marie-Elise
ME
Funk
Christoph
C
D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D002839:Chromans / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004347:Drug Interactions; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077340:Fluvastatin; D015248:Gemfibrozil / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000378:metabolism / Q000494:pharmacology; D007211:Indoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D017035:Pravastatin / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D019821:Simvastatin / Q000378:metabolism / Q000494:pharmacology; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013656:Taurocholic Acid / Q000378:metabolism / Q000494:pharmacology; D045162:Thiazolidinediones / Q000378:metabolism / Q000494:pharmacology; D000077288:Troglitazone
D000924:Anticholesteremic Agents; D002839:Chromans; D005229:Fatty Acids, Monounsaturated; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007211:Indoles; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011994:Recombinant Proteins; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C450859:SLCO2B1 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D045162:Thiazolidinediones; D004970:Estrone; D000077340:Fluvastatin; D013656:Taurocholic Acid; D019821:Simvastatin; D000077288:Troglitazone; D017035:Pravastatin; D015248:Gemfibrozil; C017296:estrone sulfate