Absorption, biliary excretion, and metabolism of a new cholelitholytic agent, ursodeoxycholyl N-carboxymethylglycine and its esters in rats.
Intestinal absorption, biliary excretion and metabolism of a calcium gallstone dissolving agent, [11,12-3H]ursodeoxycholyl-N-carboxymethylglycine (UDC-CMG) and its monoethyl, diethyl and dipivaloyloxyethyl esters (UDC-CMG-Et, UDC-CMG-Et2 and UDC-CMG-PV2) were studied in bile duct cannulated rats. Biliary recovery of [3H]-labeled UDC-CMG, UDC-CMG-Et and UDC-CMG-Et2 after intraduodenal administration were 65%, 80%, 98%, respectively. Radio-thin layer chromatography analysis of the bile revealed that UDC-CMG didn't undergo any biotransformation during administration and excretion. About 80% and 20% of radioactivity recovered in the bile was identified as UDC-CMG-Et and UDC-CMG, respectively, after intraduodenal administrations of [3H]UDC-CMG-Et2 and [3H]UDC-CMG-Et. The administered intact UDC-CMG-Et2 was not found in the bile. Intraduodenally administered [3H]UDC-CMG-PV2 was rapidly recovered in the bile. The total recovery rate was 78% within a 24 h period. More than 80% of the radioactivity recovered in the bile was found as UDC-CMG. Lesser amounts of the monopivaloyloxyethyl ester of UDC-CMG were also found, but intact UDC-CMG-PV2 was not detected in the bile as in the case of UDC-CMG-Et2. Among the esters of UDC-CMG investigated in the present studies, only UDC-CMG-PV2 was excreted in the bile mainly as the perhydrolyzed form, UDC-CMG. These results suggest the usefulness of UDC-CMG-PV2 as the pro-drug in calcium gallstone dissolution therapy.
Hatono
S
S
Wakunaga Pharmaceutical Co., Ltd., Hiroshima, Japan.
Yoshida
H
H
Matsunami
M
M
Ide
Y
Y
Matsuda
K
K
Yatsunami
T
T
Fuwa
T
T
Kihira
K
K
Kuramoto
T
T
Hoshita
T
T
D000818:Animals; D001646:Bile / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002769:Cholelithiasis / Q000188:drug therapy; D007408:Intestinal Absorption; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014316:Tritium; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D014316:Tritium; D014580:Ursodeoxycholic Acid; C075007:ursodeoxycholyl N-carboxymethylglycine; D002118:Calcium