Pharmacokinetics and dynamics of penbutolol in humans: Evidence for pathway-specific stereoselective clearance

Summary The pharmacokinetics and dynamics of thed- andl-isomers of the beta-adrenergic blocking agent penbutolol were investigated in healthy human volunteers. In Study One, subjects received a single 40-mg oral dose ofl-penbutolol (the pharmacologically active stereoisomer), and matching placebo on two occasions. A mean peak serum penbutolol concentration of 268 ng/ml was reached at 0.9 h after dosing. Elimination half-life averaged 1.6 h, and total clearance 16.6 ml/min per kg body weight. Changes in blood pressure, ventricular rate, and rate of circumferential fiber shortening (Vcf) did not differ betweenl-penbutolol and placebo. In Study Two, subjects received 40 mgd-penbutolo,l-penbutolol, and placebo on three occasions. Total clearance ofd-penbutolol was higher than for thel-isomer (43.7 vs 15.9 ml/min/kg;P<0.01); this was reflected in correspondingly increased area under the serum concentration curve for conjugates of the oxidized metabolite 4-hydroxy penbutolol (2.25 vs 0.66 µg/ml×h;P<0.005). In contrast, direct conjugates ofl-penbutolol achieved higher serum concentrations than conjugates ofd-penbutolol. Alterations in blood pressure, ventricular rate, and Vcf ford-penbutolol,l-penbutolol, and placebo were quantitatively small. Thus the clearance of penbutolol after oral administration in humans is stereoselective, but the oxidative pathway is more stereosensitive than the parallel conjugative pathway. Penbutolol causes minimal alterations in parameters of cardiac function after single 40-mg doses in healthy humans.Abbreviations AUC Area under the curve - d Dextro - HPLC High pressure liquid chromatography - l Levo - Vcf Rate of circumferential fiber shortening - t1/2 Elimination half-lifeSupported in part by Grant Oc/10 6-4 from Deutsche Forschungsgemeinschaft, by Hoechst AG, Frankfurt, Federal Republic of Germany; and by Grant MH-34223 from the United States Public Health ServiceIn part presented at the 50th Jahrestagung der Deutschen Gesellschaft für Herz- und Kreislaufforschung, Mannheim, 1984.