Rats with portacaval shunt as a potential experimental pharmacokinetic model for liver cirrhosis: application to carvedilol stereopharmacokinetics.
As an experimental model for reduced liver function rats with surgical portacaval shunts (pcs) may be used. Carvedilol, a nonselective beta-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.
Stahl
E
E
Department of Pharmacology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
Baumgartner
U
U
Henke
D
D
Schölmerich
J
J
Mutschler
E
E
Spahn-Langguth
H
H
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000818:Animals; D001646:Bile / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002227:Carbazoles / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D000077261:Carvedilol; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D011167:Portacaval Shunt, Surgical; D011412:Propanolamines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014018:Tissue Distribution
D000319:Adrenergic beta-Antagonists; D001798:Blood Proteins; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol