PT  - JOURNAL ARTICLE
AU  - Furlan, Valerie
AU  - Demirdjian, Sylvie
AU  - Bourdon, Olivier
AU  - Magdalou, Jacques
AU  - Taburet, Anne-Marie
TI  - Glucuronidation of Drugs by Hepatic Microsomes Derived from Healthy and Cirrhotic Human Livers
DP  - 1999 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1169--1175
VI  - 289
IP  - 2
4099  - http://jpet.aspetjournals.org/content/289/2/1169.short
4100  - http://jpet.aspetjournals.org/content/289/2/1169.full
SO  - J Pharmacol Exp Ther1999 May 01; 289
AB  - Pharmacokinetic studies demonstrated that the decrease in drug biotransformation in hepatic failure depends on the metabolic pathways involved. To test whether glucuronidation reactions supported by UDP-glucuronosyltransferases are differentially affected in such conditions, we investigated the in vitro glucuronidation of four selected drugs and xenobiotics (zidovudine, oxazepam, lamotrigine, and umbelliferone) by using microsomes from human healthy and unhealthy (cirrhosis, hepatitis) livers as enzyme sources. Theses substances are glucuronidated by several UDP-glucuronosyltransferase isoforms. Lidocaine N-deethylation activity measured concomitantly was used as a positive control, because the inhibition of this reaction in patients with hepatic diseases is well documented. The metabolic clearances of zidovudine and lidocaine were decreased significantly in liver cirrhosis (0.17 versus 0.37 μl/min/mg protein and 0.40 versus 2.73 μl/min/mg protein, respectively) as a consequence of a decrease of their corresponding V max of metabolism. By contrast, the metabolic clearances of oxazepam, umbelliferone, and lamotrigine glucuronidation remained unchanged. Previous studies reported that the in vivo oral clearances of zidovudine and lidocaine were decreased by 70% and 60%, respectively, in cirrhotic livers, whereas those of lamotrigine and oxazepam were not affected. Consequently, it is likely that the in vitro metabolic data, which support the in vivo results, therefore could contribute to reasonably predict the level of impairment of hepatic clearance in patients with liver cirrhosis. The American Society for Pharmacology and Experimental Therapeutics