Glucuronidation Converting Methyl 1-(3,4-Dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate(S-8921)to a Potent Apical Sodium-Dependent Bile Acid Transporter Inhibitor,Resulting in a Hypocholesterolemic Action

摘要

Methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate(S-8921)is a novel inhibitor of the ileal apical sodium-dependent bile acid transporter(ASBT/SLC10A2)developed for the treatment of hypercholesterolemia.The present study investigated the hypocholesterolemic action of S-8921 glucuronide(S-8921G)in rats.The plasma concentration of S-8921G was higher than that of S-8921 after single oral administration of S-8921 in normal rats,and S-8921G was excreted into the bile(13% dose).Oral administration of either S-8921 or S-8921G reduced the serum total cholesterol,particularly nonhigh-density lipoprotein cholesterol,in hypercholesterolemic normal rats.In Gunn rats devoid of UDP glucuronosyltransferase-1A activity,S-8921G was undetectable both in the plasma and bile specimens,and only S-8921G administration significantly reduced the serum non-high-density lipoprotein cholesterol.An in vitro inhibition study showed that glucuronidation converts S-8921 to a 6000-fold more potent inhibitor of human ASBT(K_i,=18 nM versus 109 mu M).S-8921G was detected both in the portal plasma and loop when S-8921 was administered into the loop of the rat jejunum,although the cumulative amount of S-8921G recovered in the bile was 5-fold greater than that in the loop.The uptake of S-8921G by freshly prepared rat hepatocytes was saturable,and sodium-dependent and-independent systems were involved.Organic anions,such as bromosulfophthalein,estrone 3-sulfate,and taurocholic acid,inhibited the uptake.These results suggest that UDP glucuronosyltransferase-1 isoforms play a critical role in the hypocholesterolemic action of S-8921 by converting S-8921 to a more potent ASBT inhibitor,and organic anion transporter(s)are also involved in its pharmacological action through the biliary excretion of S-8921G.