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Exhalation of 14CO2 in breath has been used to assess the rate of hepatic demethylation of (14C-dimethyl)aminopyrine, but due to the complexity of aminopyrine metabolism the pharmacokinetics of the procedure are insufficiently understood. Therefore, studies were performed in five individuals after oral administration of (14C-methoxy)glycodiazine, a model substance with relatively simple kinetic properties. Plasma concentrations of the drug and urinary output of its metabolites measured by high pressure liquid chromatography were analysed by a two-compartment open model. The terminal disappearance of 14CO2 from breath was practically identical with the terminal disappearance of glycodiazine from plasma, which could be correlated with the plasma clearance of free glycodiazine. The mean transit time of 14C-atoms from plasma to breath was 3 h. These results contribute to the pharmacokinetic basis for use of 14C-demethylation breath tests. In particular, they are consistent with the hypothesis that 14CO2-breath analysis may be used to assess certain pharmacokinetic parameters of appropriately labelled test compounds. These parameters may not necessarily be a direct reflection of the rate of demethylation.

Bopindolol has beta-blocking effects for 96 hr despite a 4-hr t1/2. 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 beta-adrenoceptor blocking material by radioreceptor assay gave identical results. The t1/2 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 t1/2s. 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 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 same order as that from in vitro radioligand studies.