Premium
Rats with portacaval shunt as a potential experimental pharmacokinetic model for liver cirrhosis: Application to carvedilol stereopharmacokinetics
Author(s) -
Stahl Elke,
Baumgartner Ulrich,
Henke Dorit,
Schölmerich Jürgen,
Mutschler Ernst,
SpahnLangguth Hildegard
Publication year - 1993
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530050102
Subject(s) - carvedilol , chemistry , pharmacokinetics , portacaval shunt , stereoselectivity , pharmacology , enantiomer , antagonist , drug metabolism , cirrhosis , metabolism , liver function , endocrinology , medicine , portal hypertension , receptor , biochemistry , stereochemistry , heart failure , catalysis
As an experimental model for reduced liver function rats with surgical portacaval shunts (pcs) may be used. Carvedilol, a nonselective β‐adrenoceptor antagonist with vasodilating activity, is extensively metabolised by phase I as well as phase II pathways. In order to study the stereoselective pharmacokinetics of carvedilol in liver disease, pcs and control rats were given rac‐carvedilol intravenously and p.o. The carvedilol enantiomers and their conjugates were assayed in plasma, urine, and bile. Carvedilol was highly bound to plasma proteins; binding was reduced by pcs. In all groups, the plasma concentrations of (R)‐carvedilol exceeded those of (S)‐carvedilol significantly. In comparison to the control group the plasma concentrations of both enantiomers increased after pcs, while the difference between the stereoisomers decreased. The total clearance decreased proportionally to the decrease in liver weight (30%). Both the apparent oral clearance, as well as its stereoselectivity were reduced, by up to 90 and 43%, respectively. The biliary clearance of the parent drug after i.v. dosage increased in rats with pcs due to the reduced hepatic metabolism. © 1993 Wiley‐Liss, Inc.