Induction and inhibition of cicletanine metabolism in cultured hepatocytes and liver microsomes from rats

• Published in: Fundamental & clinical pharmacology Vol. 14; no. 5; pp. 509 - 518
• Main Authors: Menard, Christophe, Lamiable, Denis, Vistelle, Richard, Morin, Elisabeth, Ratanasavanh, Damrong
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-09-2000; Blackwell
• Subjects: Animals; Antihypertensive agents; Antihypertensive Agents - metabolism; Biological and medical sciences; Cardiovascular system; Cells, Cultured; cicletanine; conjugation; Glucuronides - metabolism; Glucuronosyltransferase - metabolism; Hepatocytes - metabolism; induction; inhibition; Isoenzymes - metabolism; Male; Medical sciences; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Pharmacology. Drug treatments; Pyridines - metabolism; Rats; Rats, Sprague-Dawley; Somatomedins; Substrate Specificity; Sulfotransferases - metabolism; Cell culture; Rat; UDP-glucuronosyltransferase; Digestive system; Enzyme; Isozyme; Transferases; Liver; Glycosyltransferases; Rodentia; Glucuronic acid conjugation; Metabolism; In vitro; Stereoselectivity; Vertebrata; Mammalia; Hepatocyte; Animal; Enantiomer; Cicletanine; Antihypertensive agent; Hexosyltransferases
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1111/j.1472-8206.2000.tb00434.x

— Cicletanine, a racemic furopyridine derivative synthesized as racemate, is used as an antihypertensive agent. Its two enantiomers are involved in the pharmacological effects of the drug. Cicletanine is metabolized by conjugation enzyme systems (phase II) into sulfoconjugated or glucuroconjugated enantiomers. This study reports on the use of both the induction with 3‐methylcholanthrene (3‐MC) or phenobarbital (PB) and inhibition with selective compounds to determine and identify UGT isoenzymes involved in the metabolism of cicletanine enantiomers. PB and 3‐MC both enhanced the cicletanine enantiomer glucuronidation. These two compounds being known as inducing agents of UGT2B1 and UGT1A6 isoforms, respectively, this suggests an implication of UGT2B1 and UGTIA6 isoforms in the metabolism of the two cicletanine enantiomers: (+)‐cicletanine and (‐)‐cicletanine. The use of selective compounds for inhibition study evidenced, in addition to UGT2BI and UGT1A6 isoforms, the involvement of other UGT isoforms such as UGTIAI, UGT2B7 and UGT2B15 in cicletanine metabolism.