Stereoselective disposition and tissue distribution of carvedilol enantiomers in rats.
After intravenous bolus injection of rac-carvedilol at 2 mg/kg to the rat, the (+)-(R)- and (-)-(S)-enantiomer levels in the blood and tissues (liver, kidney, heart, muscle, spleen, and aorta) were measured by stereospecific HPLC assay. As compared with the (+)-(R), the (-)-(S) had a larger Vdss (3.32 vs. 2.21 liter/kg), MRT (33.4 vs. 25.6 min), and CLtot (96.1 vs. 83.8 ml/min/kg). AUC comparison after iv and po administration showed systemic bioavailability of the (-)-(S) to be about half that of its antipode, explained by the fact that the free fraction of the (-)-(S) in blood was 1.65-fold greater than that of the (+)-(R). Tissue-to-blood partition coefficient values for the (-)-(S) were 1.6- to 2.1-fold greater than those for the (+)-(R) in all tissues, showing that the (-)-(S) accumulates more extensively in the tissues. These results were consistent with the greater Vdss for the (-)-(S) estimated from systemic blood data. The stereoselective tissue distribution of carvedilol enantiomers results from an enantiomeric difference in plasma protein binding rather than in tissue binding.
Fujimaki
M
M
Exploratory Research Laboratories III, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D002227:Carbazoles / Q000493:pharmacokinetics*; D000077261:Carvedilol; D008297:Male; D011412:Propanolamines / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D014018:Tissue Distribution; D014665:Vasodilator Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D002227:Carbazoles; D011412:Propanolamines; D014665:Vasodilator Agents; D000077261:Carvedilol