Nifedipine kinetics in the rat and relationship between its serum concentrations and uterine and cardiovascular effects.

1. The kinetics of nifedipine and the relationship between its serum concentration and uterine and cardiovascular effects were investigated in 3 groups of animals. These were ovariectomized (ovx) anaesthetized non-pregnant rats following bolus i.v. injection (400 micrograms kg-1) and during 300 min infusion (10 micrograms kg-1 min-1) and ovx, progesterone-treated late pregnant rats during infusion. Also, the kinetics were determined in ovary-intact late pregnant rats following bolus i.v. injection (400 micrograms kg-1). 2. Measurement of serum nifedipine concentrations after bolus i.v. injection in ovx non-pregnant rats showed a biexponential decay with time from which the following parameters were calculated: V beta = 300 +/- 30 ml kg-1; rate constants k12 = 0.51 +/- 0.18 min-1; k21 = 0.07 +/- 0.02 min-1; ke1 = 0.10 +/- 0.05 min-1; elimination clearance = 2.4 +/- 0.2 (ml min-1) kg-1; t1/2 alpha = 2.5 +/- 1.0 min; t1/2 beta = 102 +/- 15 min. In intact pregnant rats, a biexponential decay of serum nifedipine concentrations with time was also observed after bolus i.v. administration with similar parameters to non-pregnant animals. These kinetic parameters, used to calculate serum nifedipine concentrations obtained during infusion, predicted values similar to experimental values for 180 min, but thereafter slightly underestimated experimental values. 3. Immediate reductions in uterine contractions, mean blood pressure and heart rate were observed following bolus i.v. injection of nifedipine to ovx non-pregnant rats, with returns towards control values as serum nifedipine concentrations declined. IC15 values (15% change from baseline), calculated from log10 serum concentration-response curves, of 0.3 +/- 0.05 micrograms ml-1 for inhibition of uterine contractions, 0.8 +/- 0.3 micrograms ml-1 for depression of blood pressure and 3.8 +/- 1.0 micrograms ml-1 for reduction in heart rate were obtained. 4. In ovx non-pregnant rats, nifedipine infusion produced a maximum reduction in integral of uterine contractions of 70% by 120 min and a maximum reduction of 15% in heart rate. Mean blood pressure was not significantly different from vehicle-treated rats. IC15 values were 0.7 +/- 0.1 micrograms ml-1 and 2.8 +/- 0.6 micrograms ml-1 for inhibition of uterine contractions and heart rate respectively. 5. In ovx, progesterone-treated late pregnant rats, nifedipine infusion produced similar serum concentrations to those of non-pregnant rats but completely abolished uterine contractions by 70 min. Maximum reductions of 30% in heart rate and blood pressure were observed.(ABSTRACT TRUNCATED AT 400 WORDS)