Rats with portacaval shunt as a potential experimental pharmacokinetic model for liver cirrhosis: Application to carvedilol stereopharmacokinetics

Abstract

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.

Simultaneous quantification of carvedilol and its metabolites in rat plasma by ultra performance liquid chromatography tandem mass spectrometry and pharmacokinetic application

“…When CAR was given orally, the elimination halflife (t 1/2 ) usually varied between 3.1 and 18 h [17,[33][34][35][36][37]. In this study, the t 1/2 was 3.2 h after administration of a 1.5-1.8 mg doses for each rat in non-compartment model analysis, which is in good agreement with the reported value.…”

“…There are few reports on carvedilol pharmacokinetic study in rats [17,[33][34][35][36][37]. When CAR was given orally, the elimination halflife (t 1/2 ) usually varied between 3.1 and 18 h [17,[33][34][35][36][37].…”

Enantioselective analysis of (R)- and (S)-carvedilol in human plasma by high-performance liquid chromatography

“…In some methods the enantiomers of carvedilol are derivatized with enantiomerically pure reagents such as (+)-(R)-phenylethyl isocyanate [13], 2,3,4,6-tetra-O-acetyl-/?-D-glucopyranosylisothiocyanate (GITC) [14], or (+)-(S)-naproxen chloride [15] and separated 'indirectly' as diastereomers by HPLC. 'Direct' separation of underivatized carvedilol enantiomers has been accomplished on chiral stationary phases such as Chiracel OF [8].…”

Propranolol stereoisomer plasma concentrations and portal haemodynamic response in patients with liver cirrhosis

“…It has been shown for carvedilol that such a metabolic stereoselectivity can be greatly altered in patients with liver cirrhosis as compared to healthy subjects 19 . These results have been substantiated in rats that underwent portacaval shunting 20 . Certain studies have used R‐propranolol as a model drug for investigating reduced hepatic drug clearance in patients with cirrhosis 21 , .…”