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Simultaneous modeling of bopindolol kinetics and dynamics
Author(s) -
Platzer Rudolf,
Galeazzi Renato L,
Niederberger Werner,
Rosenthaler Joachim
Publication year - 1984
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1984.130
Subject(s) - chemistry , pindolol , metabolite , active metabolite , pharmacokinetics , in vivo , plasma concentration , kinetics , medicine , dissociation constant , lipophilicity , endocrinology , receptor , pharmacology , stereochemistry , biochemistry , physics , quantum mechanics , microbiology and biotechnology , biology
Bopindolol has β‐blocking effects for 96 hr despite a 4‐hr t½. 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 six 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 hr. Chemical assay by HPLC and determination of total active β‐adrenoceptor blocking material by radioreceptor assay gave identical results. The t½ was 4 to 5 hr. Effects, measured as reduction in exercise‐induced tachycardia (REIT) and as the isoproterenol dose ratio (DR — 1), were followed for 96 hr. 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 t½s. Parameter estimates for kinetic end 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 hr. 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 pmolll (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 same order as that from in vitro radioligand studies. Clinical Pharmacology and Therapeutics (1984) 36, 5–13; doi: 10.1038/clpt.1984.130