Received for publication September 15, 2006.
Revised April 23, 2007.
Accepted for publication April 25, 2007.

SUBSTRATE DEPENDENT DRUG-DRUG INTERACTIONS BETWEEN GEMFIBROZIL, FLUVASTATIN AND OTHER OATP SUBSTRATES ON OATP1B1, OATP2B1 AND OATP1B3

Abstract

Hepatic uptake carriers of the OATP family of solute carriers are more and more recognized to be 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 CHO or HEK293 cells expressing either OATP1B1 (Km=1.4-3.5 µmol/L), OATP2B1 (Km=0.7-0.8 µmol/L) or OATP1B3, showed significant fluvastatin uptake relative to control cells. For OATP1B1 the inhibition by gemfibrozil was substrate-dependent, the transport of fluvastatin (IC50 of 63 µmol/L), pravastatin, simvastatin and taurocholate was inhibited by gemfibrozil, while transport of estrone-3-sulfate and troglitazone sulfate (both used at 3 µmol/L) was not affected. The OATP1B1-, but not OATP2B1-mediated transport of estrone-3-sulfate displayed a biphasic saturation kinetics, with two distinct affinity components for estrone-3-sulfate (0.23 µmol/L and 45 µmol/L). 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 µmol/L), respectively, while only a small inhibitory effect by gemfibrozil (200 µmol/L) 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 like freshly isolated primary hepatocytes. Therefore selection of substrate, substrate concentration and in vitro transport system is critical for the conduct of in vitro interaction studies involving individual liver OATP carriers.

Key words: active transport, drug-drug interactions, hepatic uptake, hepatobiliary transport, organic anion transport, transporters

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