Carvedilol Stereopharmacokinetics in Rats: Affinities to Blood Constituents and Tissues

Carvedilol, a lipophilic β‐adrenoceptor antagonist with vasodilating activities, is characterized by a high as well as stereoselective metabolic clearance and distribution volume. Tissue distribution of carvedilol enantiomers and their conjugates were determined under steady‐state conditions in rats (p.o., 10 mg/kg, repetitive dosage; n = 5) and after single i.v. administration in control rats and rats with surgical portacaval shunt (pcs) (10 mg/kg; n = 3 each group). In addition, in vitro plasma protein binding was evaluated. ‐ The plasma protein binding of carvedilol in rats is > 98% for total plasma (tp) and > 96% for rat serum albumin (rsa) solution (4%), with enantioselectivity ratios of 1.53 (tp) and 1.27 (rsa). Significantly higher unbound fractions were observed in pcs rats, in part due to reduced protein concentrations. ‐ 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 all tissues (heart, liver, kidneys, lung, spleen, muscle, and adipose tissue), 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 accordance with its higher unbound fraction in plasma. Carvedilol accumulated predominantly in the highly perfused and/or eliminating organs liver, kidneys, and lung (tissue/plasma ratios; lung: S 76, R 34; liver: S 21, R 5; kidney: S 8, R 3). A similarly enantioselective distribution 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 higher in these rats. The kidney/plasma ratio was elevated approximately 2‐fold for the parent compound (control: S 7, R 2; pcs: S 14, R 4) and 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, with significantly smaller concentrations than those of the aglycones and with varying stereoselectivities. Stereopharmakokinetik von Carvedilol bei der Ratte: Affinität zu Blutbestandteilen und Geweben Carvedilol, ein lipophiler β‐Adrenozeptor‐Antagonist mit zusätzlicher vasodilatierender Wirkung, ist charakterisiert durch eine hohe und stereoselektive metabolische Clearance sowie ein hohes und stereoselektives Verteilungsvolumen. Die Verteilung der Enantiomere von Carve