The influence of chronic verapamil treatment on antipyrine elimination was studied in eight angina patients. Antipyrine half-life (mean ± s.d.) was 13.1 ± 1.15 h at the start of therapy and 16.6 ± 3.05 h (P < 0.05) during chronic oral administration of verapamil (80 -120 mg four or three times daily for 4 to 7 months). There was a significant decrease in antipyrine clearance (mean ± s.d, 43.2 ± 16.8 ml min-' vs 28.7 ± 16.6 ml min-', P < 0.01) while the change of distribution volume was insignificant. Verapamil elimination was also found to be impaired after chronic dosing as compared to single administration. Half-lives measured from the concentration vs time and urinary excretion rate vs time curves were both prolonged and oral clearance was decreased. Our results suggest that the inhibition of drug-metabolizing enzymes accounts for the impairment of verapamil elimination on chronic administration.

No abstract

No abstract

The use of a function to fit blood concentration-time data points is equivalent, under certain assumptions, to specifying a model of the distribution of residence times of the drug molecules in the body (stochastic pharmacokinetic model). An empirical density function of the Weibull type is offered to describe this distribution. The model gives the following disposition function describing the time course of the drug concentrations in blood after an intravenous bolus input: C delta (t) = D/CLs lambda ts-1exp(-lambda ts). It contains only three parameters: lambda is like an 'elimination rate constant' in the single-exponential model into which the Weibull function reduces when the shape parameters becomes equal to unity; CL is the conventional systemic drug clearance, and, D is the dose injected. The Weibull function gives an analytical solution of the convolution integral for zero-order input, thereby permitting use of the model for intravenous infusion data and for extravascular administration, when the absorption may be considered to be zero-order. Using examples from the literature it is shown that in some cases the Weibull function gives a better fit than may be obtained with two- and three-exponential or gamma functions.

1 The possibility of development of tolerance to the anti-ischaemic and anti-anginal effects of nifedipine during sustained administration for 2 months was studied in 15 patients with stable angina pectoris by means of repeated exercise tests on a treadmill. 2 After acute administration of nifedipine (20-30 mg) substantial anti-ischaemic and anti-anginal effects lasted for at least 4 h in all patients. 3 During sustained nifedipine treatment with a dose schedule which provided continuous anti-ischaemic effect during a day (mean daily dose 82.7 ± 6.0 mg, range 60-120 mg) a substantial attenuation of this effect was registered. The duration of the anti-ischaemic effect was 5.4 ± 0.3 h after acute administration, decreasing significantly to 3.6 ± 0.4 h during sustained administration. 4 The attenuation of the nifedipine effect was not associated with worsening of the patients' condition. 5 Plasma concentrations of nifedipine and its metabolite were similar after acute administration and during sustained treatment. Protein binding of nifedipine also remained constant during the study. 6 There was marked interindividual variation in the degree of attenuation of the nifedipine effect during sustained administration. In five patients nearly complete loss of nifedipine efficacy was registered. Eight to ten days after stopping regular administration of nifedipine only partial restoration of nifedipine effect was observed. 7 We conclude that during sustained nifedipine administration tolerance to its antiischaemic, anti-anginal and circulatory effects develops in a substantial number of patients with stable angina pectoris.