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Stereoselective disposition and tissue distribution of carvedilol enantiomers in rats
Author(s) -
Fujimaki Masayoshi
Publication year - 1992
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.530040304
Subject(s) - chemistry , carvedilol , enantiomer , stereoselectivity , bioavailability , tissue distribution , pharmacokinetics , kidney , high performance liquid chromatography , spleen , stereospecificity , pharmacology , free fraction , partition coefficient , chromatography , stereochemistry , plasma protein binding , endocrinology , medicine , biochemistry , heart failure , catalysis
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 Vd ss (3.32 vs. 2.21 liter/kg), MRT (33.4 vs. 25.6 min), and CL tot (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 Vd ss 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. © 1992 Wiley‐Liss, Inc.