DIRECT ENANTIOSELECTIVE DETERMINATION OF (R)-PROPRANOLOL AND (S)-PROPRANOLOL IN HUMAN PLASMA - APPLICATION TO PHARMACOKINETIC STUDIES

In order to examine possible drug interactions of (R)- and (S)-propranolol a randomized, double blind. crossover study has been performed, administering orally single doses of 40 mg (R,S)- and of 20 mg (S)-propranolol.HCl three limes daily over a week to reach steady start: conditions. After the first single dose of 40 mg (R,S)-propranolol.HCl, the AUC(0-x) and C-max values of the (S)-isomer were greater than those of the (R)-isomer: the ratio of AUC((S)) over AUC((R)) was 1.77 (P<0.05) and that of C-max 1.57 (P<0.01). When (S)-propranolol.HCl was given as a single 20 mg dose, the AUC((S)) value was a factor of 0.55 lower than after administration of 40 mg (R,S)-propranolol.HCl. At steady state, the AUC of (S)-propranolol was 1.52 times higher (P<0.01) than that of the (R)-isomer after administration of 40 mg racemate, and comparing the (S)-isomer, the ratio was 1.21. Following administration of the first single dose of 40 mg of the racemate, the mean (SD) clearance of the (R)- and (S)-isomers was 110 (84) and 61 (37) ml min(-1) kg(-1), respectively; at steady state these values were 89 (55) and 57 (37) ml min(-1) kg(-1), respectively. Respective values for (S)-propranolol after single isomer administration (20 mg) were 86 (36) and 57 (25) ml min(-1) kg(-1) in single dose and steady state situations. The data are based on the quantitative analysis of (R)- and (S)-propranolol in plasma. A sensitive enantioselective LC-bioassay based on the formation of the (R)- and (S)-propranolol-oxazolidine-2-one and resolution of these derivatives on a (R,R)-dinitrobenzoyl-diaminocyclohexane ((R,R)-DNB-DACH) chiral, stationary phase was developed, using dichloromethane-methanol (99.75:0.25, v/v) as mobile phase, with fluorimetric detection.