Simultaneous modeling of bopindolol kinetics and dynamics

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Abstract
Bopindolol has .beta.-blocking effects for 96 h despite a 4-h t1/2 [half-life]. To investigate the concentration-effect relationship after single and repeated doses, 2-mg oral doses were given once and then daily for 13 days to 6 healthy subjects. In plasma, no unchanged drug, (only the hydrolysis product of bopindolol, referred to as bopindolol concentration) was detectable or could be measured up to 24 h. Chemical assay by HPLC [high-performance liquid chromatography] and determination of total active .beta.-adrenoceptor blocking material by radioreceptor assay gave identical results. The t1/2 was 4-5 h. Effects, measured as reduction in exercise-induced tachycardia (REIT) and as the isoproterenol dose ratio (DR-1), were followed for 96 h. The concentration of bopindolol in plasma (predicted with a one-compartment body model) could be related to the measured effects by classic effect models for 20 t1/2. Parameter estimates for kinetic and effect models did not differ after single and repeated doses. With the parameters from the single-dose experiment, the time course of the plasma concentration and the effects after the multiple-dose experiment could be adequately predicted for 24 and 96 h. A deep compartment, an active metabolite or irreversible destruction of the receptor (accounting for the persistence of the effect) could be excluded. The dissociation constant of 100 pmol/l (from DR-1/concentration) and the minimal effective plasma concentration (from REIT/log concentration) of 1 pmol/l suggest that enough receptors are occupied at chemically unmeasurable levels in plasma to induce an effect. The dissociation constant determined in vivo is of the some order as that from in vitro radioligand studies.