Stereoselective Disposition and Glucuronidation of Propranolol in Man

Abstract

Following oral dosing to steady state, the disposition of S(-)- and R(+)-propranolol and their corresponding glucuronide conjugates was studied in 4 healthy adults using doses from 40 to 320 mg/day of the racemate. Steady-state plasma concentrations of S(-)-propranolol and its corresponding glucuronide conjugate were greater than that for R(+)-propranolol and its corresponding conjugate. The average steady-state concentration of both enantiomers increased disproportionately to dose. There was a 52 ± 7 (mean ± SD)% decrease in the intrinsic clearance (Cl(int)) of S(-)-propranolol and a 65±22% decrease in the Cl(int) of R(+)-propranolol over the dosing range studied. The terminal elimination half-lives of S(-)-propranolol and its glucuronide conjugate were longer than for the R(+)-enantiomer at all doses. The formation of glucuronide conjugates of S(-)- and R(+)-propranolol was best described by a saturable process in all subjects. Within individuals, the ratio of V(max)/K(m) for the glucuronide conjugate of S(-)-propranolol was from 2.1- to 4.9-fold greater than for the conjugate of the R(+)-enantiomer. These studies demonstrate for the first time, that propranolol undergoes stereoselective disposition in humans.