Received for publication January 17, 2008.
Revised May 2, 2008.
Accepted for publication May 8, 2008.

Identification of the transporters involved in the hepatobiliary transport and intestinal efflux of S-8921 glucuronide, a pharmacologically active metabolite of S-8921

Abstract

The glucuronide conjugate of S-8921 (S-8921G) is a 6,000-fold more potent inhibitor of an ileal apical sodium-dependent bile acid transporter (SLC10A2) than S-8921, and is responsible for the hypocholesterolemic effect of S-8921 in rats. Since S-8921G is formed in the intestine and liver, the present study investigated the transporters involved in the secretion of S-8921G which govern its exposure to the target site and, thereby, play an important role in its pharmacological action. OATP1B1 and OATP1B3-expressing cells exhibited saturable accumulation of S-8921G with Km values (µM) of 1.9. The uptake of [¹⁴C]S-8921G by human cryopreserved hepatocytes was saturable, and sodium-independent. Comparison of protein expression between the cDNA transfectants and hepatocytes suggests that the contribution of OATP1B1, OATP1B3 and NTCP to the hepatic uptake of S-8921G is 63, 35 and 2.6%, respectively. The basal-to-apical transport of S-8921G was enhanced in MDCK cells expressing both OATP1B1 and MRP2. In Mrp2-deficient mutant rats (EHBR), the biliary excretion clearance based on the plasma concentration was 20% of the normal value, while the pharmacokinetic parameters did not show any significant change in Bcrp^-/- mice. Furthermore, the secretion clearance of S-8921G to the mucosal side was also significantly lower in everted jejunum sacs from EHBR (9.18 and 20.8 µL/min/g tissue). These results suggest that MRP2 is responsible for the secretion of S-8921G to the intestinal lumen and bile, and OATP1B1 and -1B3 account for the hepatic uptake. These transporters deliver S-8921G to the target site of its pharmacological action.

Key words: ABC transporters, biliary excretion, drug disposition, drug efflux, drug transport, hepatobiliary transport, MRP, organic anion transport, transporters