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.
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 nonhigh-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 microM). 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.
Sakamoto
Shingo
S
Developmental Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Kusuhara
Hiroyuki
H
Miyata
Kenji
K
Shimaoka
Hiroyuki
H
Kanazu
Takushi
T
Matsuo
Yumiko
Y
Nomura
Kohji
K
Okamura
Noboru
N
Hara
Seijiro
S
Horie
Kazutoshi
K
Baba
Takahiko
T
Sugiyama
Yuichi
Y
D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D014453:Glucuronosyltransferase / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy; D007408:Intestinal Absorption; D007700:Kinetics; D008297:Male; D015394:Molecular Structure; D009284:Naphthols / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011169:Portal Vein / Q000378:metabolism; D051381:Rats; D011911:Rats, Gunn; D017208:Rats, Wistar; D027981:Symporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013656:Taurocholic Acid / Q000378:metabolism; D014162:Transfection; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism*
D000924:Anticholesteremic Agents; D008076:Cholesterol, HDL; D009284:Naphthols; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter; C106517:S 8921; D014535:Uridine Diphosphate Glucuronic Acid; D013656:Taurocholic Acid; D002784:Cholesterol; D014453:Glucuronosyltransferase