Stereospecific and circadian-phase-dependent kinetic behavior of d,l-, l-, and d-propranolol in plasma, heart, and brain of light--dark-synchronized rats

In light--dark-synchronized male rats, the kinetic behavior of d,l-, l-, and d-propranolol after single (1.78 and 8.89 mg/kg) or multiple drug administration (6 X 8.89 mg/kg) was studied in plasma, heart, and brain both in the light period (L) and in the dark period (D). With either dosage regimen the kinetics of racemic propranolol displayed a temporal dependency, elimination half-lives in plasma, heart, and brain being shorter during D than during L. This was observed with the stereoisomers only after single drug application with no circadian phase dependency at steady-state concentrations. On the other hand, the kinetic behavior of l- and d-propranolol exhibited pronounced stereospecificity in that t1/2 Beta, Vdbeta, plasma clearance, and drug accumulation in heart and brain were greater for l-propranolol than for the d-isomer. Stereospecific differences in t1/2 beta and elimination rate were more pronounced during D. In the light of the flow-dependent hepatic extraction of propranolol it is unlikely that daily variations in microsomal liver enzyme activity are responsible for the chronopharmacokinetics of propranolol. It is assumed that daily variations in liver blood flow, which is more effectively reduced by beta-receptor blockade in the period of increased sympathetic tone during D, are mainly responsible for the chronopharmocokinetics of the therapeutically used d,l-propranolol.