Chronopharmacology of β-Adrenoceptor-Blocking Drugs: Pharmacokinetic and Pharmacodynamic Studies in Rats

Abstract

Specific and nonspecific effects and the pharmacokinetic behavior of β-adrenoceptor-blocking drugs of different Iipophilicity (atenolol, bupranolol, carazolol, metoprolol, ox-prenolol, practolol, propranolol, sotalol) were investigated in L-D-synchronized male rats as a function of treatment time. The studies revealed that pharmacodynamic effects on heart rate, cardiac noradrenaline turnover, and motor activity as well as pharmacokinetic parameters of racemic mixtures of β-receptor blockers display temporal variations with more pronounced pharmacological effects and shorter elimination half-lives in the dark span. Studies with the isomers of bupranolol and practolol indicate no stereospecificity in the central depressant effect; the kinetic behavior of, for example, propranolol, however, exhibits stereospecificity. The results demonstrate the importance of circadian rhythms in modifying the effects and kinetics of drugs. These findings may have therapeutic implication in human subjects.