Abstract
The glucuronide conjugate of methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921; S-8921G) is a 6000-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. Because S-8921G is formed in the intestine and liver, the present study investigated the transporters involved in the secretion of S-8921G that govern its exposure to the target site and thereby play an important role in its pharmacological action. Organic anion transporting polypeptide (OATP) 1B1- and OATP1B3-expressing cells exhibited saturable accumulation of S-8921G with Km values (micromolar) 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 Na+-taurocholate cotransporting polypeptide 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 Madin-Darby canine kidney cells expressing both OATP1B1 and multidrug resistance-associated protein (MRP) 2. In Mrp2-deficient mutant rats [Eisai hyperbilirubinemic rats (EHBR)], the biliary excretion clearance based on the plasma concentration was 20% of the normal value, whereas 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 that OATP1B1 and OATP1B3 account for the hepatic uptake. These transporters deliver S-8921G to the target site of its pharmacological action.
Footnotes
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
doi:10.1124/dmd.108.020511.
-
ABBREVIATIONS: LDL, low-density lipoprotein; S-8921, methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate; ASBT, apical sodium-dependent bile acid transporter; S-8921G, glucuronide conjugate of S-8921; UGT, UDP-glucuronosyltransferase; NTCP, Na+-taurocholate cotransporting polypeptide; OATP, organic anion transporting polypeptides; MRP, multidrug resistance-associated protein; MDCK, Madin-Darby canine kidney; EHBR, Eisai hyperbilirubinemic rats; BCRP, breast cancer resistance protein; E-sul, estrone sulfate; TCA, taurocholic acid; E217βG, estradiol-17β-d-glucuronide; CCK, cholecystokinin; SD, Sprague-Dawley; HEK, human embryonic kidney; TBS-T, Tris-buffered saline/Tween 20; AUC, area under the plasma concentration-time curve; KRB, Krebs-Ringer buffer.
- Received January 17, 2008.
- Accepted May 8, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|