Comparative In Vivo and In Vitro Studies of Phenytoin Protein Binding and In Vitro Lipolysis in Plasma of Pregnant and Nonpregnant Rats

Chou, Ruby C.; Levy, Gerhard

doi:10.1002/jps.2600730824

Cited by 5 publications

(1 citation statement)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, for a drug as extensively protein-bound as nifedipine, a relatively small change in serum binding protein concentration would have a marked effect on serum unbound drug concentrations. An increase in unbound fraction of the drug in serum might be accompanied by an increase in elimination clearance resulting in decreased serum total drug concentration (Chou & Levy, 1984;Levy, 1984). No significant differences in kinetic parameters of total serum drug were observed between pregnant and non-pregnant rats.…”

Section: Pharmacokineticsmentioning

confidence: 99%

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

Downing¹,

Hollingsworth²

1988

British J Pharmacology

View full text Add to dashboard Cite

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.

show abstract

Section: Pharmacokineticsmentioning

confidence: 99%