title: Identification of the transporters involved in the hepatobiliary transport and intestinal efflux of methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921) glucuronide, a pharmacologically active metabolite of S-8921.
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 K(m) 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 microl/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.
authors.affiliation: Developmental Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Horie
authors.forename: Kohji
authors.initials: K
authors.lastname: Takahashi
authors.forename: Takahiko
authors.initials: T
authors.lastname: Baba
authors.forename: Jun
authors.initials: J
authors.lastname: Ishizaki
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001659:Biliary Tract / Q000378:metabolism*; D015153:Blotting, Western; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002478:Cells, Cultured; D004285:Dogs; D020719:Glucuronides / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D009284:Naphthols / Q000493:pharmacokinetics*; D027361:Organic Anion Transporters / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C000715087:ABCC2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D002250:Carbon Radioisotopes; D020719:Glucuronides; D000089762:Multidrug Resistance-Associated Protein 2; D009284:Naphthols; D027361:Organic Anion Transporters; C106517:S 8921