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

Abstract

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 yg kg-1) and during 300 min infusion (10pgkg-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 pg 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: Ve = 300 + 30mlkg-1; rate constants k12 = 0.51 + 0.18min-1; k21 = 0.07 + 0.02min-1; kel = 0.10 + 0.05 min1; elimination clearance = 2.4 + 0.2 (ml min 1)kg-1; t1/2_ = 2.5 + 1.0min; t 112, = 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. ICI5 values (15% change from baseline), calculated from log10 serum concentration-response curves, of 0.3 + 0.05 pg ml-I for inhibition of uterine contractions, 0.8 + 0.3pgml -1 for depression of blood pressure and 3.8 + 1.0 Yg ml1 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. IC1_ values were 0.7 + 0.1 pg ml1 and 2.8 + 0.6.pg ml-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 70min.Maximum reductions of 30% in heart rate and blood pressure were observed. IC1S values were 0.5 + 0.1ygml-1 for uterine contractions, 0.9 + 0.3lpgmlP1 for blood pressure and 1.2 ± 0.3 pg ml -1 for heart rate. 6 The findings suggest that the kinetics of nifedipine are similar in pregnant and non-pregnant rats and support the idea that the drug exerts a slight selectivity for uterine inhibition relative to cardiovascular effects. The uterus of the late pregnant rat appears to be more sensitive to nifedipine than that of the non-pregnant animal.

Effects of calcium channel blockers on the development of early rat postimplantation embryos in culture

“…Such differences have to be considered since we want to compare free concentrations in humans and rats in vivo with that in cow serum in vitro. Species differences in protein binding have been documented for NIF at least between man and dog (Rosenkranz et al 1974), but not between rat and man (cited in Downing and Hollingsworth 1988), and for DIL, i.e. with 300 ng/ml, between rat plasma (84%) and human plasma (63%) and human serum albumin (40%) and bovine serum albumin (66%) (Nakamura et al 1987).…”

The influence of oestrogen and progesterone on the actions of two calcium entry blockers in the rat uterus

“…), subjected to bilateral ovariectomy by dorsal laparotomy and equipped with a small latex pressure-recording bal¬ loon inserted into one uterine horn as described pre¬ viously (Downing et al 1987). The rats were then given one of the following treatments commencing on the day of surgery: (a) 0-05 ml corn oil s.c. on days 1 and 2 plus an empty s.c. implant consisting of a 5 cm length of Silastic tubing (internal diameter 1-5 mm outside diameter 200mm; Dow Corning, Midland, MI, U.S.A.) inserted at surgery (control rats); (b) 1-5 nmol oestradiol/kg (Sigma Chemical Co., Poole, Dorset, U.K.) s.c. in 005 ml corn oil on days 1 and 2 plus an empty implant s.c; (c) 005ml corn oil s.c. on days 1 and 2 plus an implant containing approximately 0-2 mmol cystalline progesterone (Sigma Chemical Co.) s.c; (d) 1-5 nmol oestradiol/ kg in 0-05 ml corn oil s.c. on days 1 and 2 plus a progesterone implant s.c.…”

“…The increase in potency of diltiazem observed in rats in late pregnancy, however, is due to factors other than oestrogen and progesterone. The lack of effect of hormonal INTRODUCTION Calcium entry blockers are potent inhibitors of ten¬ sion development by rat uterine smooth muscle in vitro (Granger, Hollingsworth & Weston, 1985, 1986Edwards, Good, Granger et al 1986) and in vivo (Abel & Hollingsworth, 1985, 1986Downing, Edwards & Hollingsworth, 1987; Hollingsworth Downing . We have recently demonstrated a twofold increase in the potency of nifedipine against uterine contractions in rats during late pregnancy compared with nonpregnant rats .…”

Modification of the myometrial relaxing effect of nifedipine in vitro and in vivo

“…We planned administration of a dose regimen via osmotic pumps which provided a plasma nifedipine concentration of ~1.5 µg/ml (estimated). Downing and Hollingsworth (1998) concluded that this plasma level of the drug did not cause significant changes in heart rate or blood pressure, but elicited a well-defined uterus-relaxing effect. We found that treatment with nifedipine alone started on pregnancy day 16 was more effective in delaying delivery than salmeterol treatment alone (in the earlier study) (Gálik et al, 2008).…”

“…The in vivo dose for the tocolytic effect was calculated by using the pharmacokinetic parameters reported for nifedipine in pregnant rats by Downing et al (Downing and Hollingsworth, 1998). We planned administration of a dose regimen via osmotic pumps which provided a plasma nifedipine concentration of ~1.5 µg/ml (estimated).…”