CARVEDILOL STEREOPHARMACOKINETICS IN RATS - AFFINITIES TO BLOOD-CONSTITUENTS AND TISSUES

Carvedilol, a lipophilic beta-adrenoceptor antagonist with vasodilatin g activities, is characterized by a high as well as stereoselective me tabolic clearance and distribution volume. Tissue distribution of carv edilol enantiomers and their conjugates were determined under steady-s tate conditions in rats (p.o., 10 mg/kg, repetitive dosage; n = 5) and after single i.v. administration in control rats and rats with surgic al portacaval shunt (pcs) (10 mg/kg; n = 3 each group). In addition, i n vitro plasma protein binding was evaluated. - The plasma protein bin ding of carvedilol in rats is > 98% for total plasma (tp) and > 96% fo r rat serum albumin (rsa) solution (4%), with enantioselectivity ratio s of 1.53 (tp) and 1.27 (rsa). Significantly higher unbound fractions were observed in pcs rats, in part due to reduced protein concentratio ns. - In contrast to plasma, where a preponderance of the R-enantiomer with an S/R ratio of 0.6 was found, S-carvedilol was predominant in a ll tissues (heart, liver, kidneys, lung, spleen, muscle, and adipose t issue), with S/R ratios of 1.3-1.4 in most of these tissues and 2.3 in liver. This preferential tissue partitioning of S-carvedilol was in a ccordance with its higher unbound fraction in plasma. Carvedilol accum ulated predominantly in the highly perfused and/or eliminating organs liver, kidneys, and lung (tissue/plasma ratios; lung: S 76, R 34; live r: S 21, R 5; kidney: S 8, R 3). A similarly enantioselective distribu tion into the heart of control as well as pcs rats was observed, where the S-enantiomer concentrations exceeded the plasma concentrations 7- fold. Probably because of the impaired liver function in pcs rats with increased importance of the renal route, kidney concentrations were h igher in these rats. The kidney/plasma ratio was elevated approximatel y 2-fold for the parent compound (control: S 7, R 2; pcs: S 14, R 4) a nd 4-fold for the R-carvedilol conjugate (control: S 2, R 1; pcs: S 3, R 4). The conjugates of carvedilol were detectable in all organs, wit h significantly smaller concentrations than those of the aglycones and with varying stereoselectivities.