Effect of type 2 diabetes mellitus on the pharmacokinetics and transplacental transfer of nifedipine in hypertensive pregnant women.

AIMS: Diabetes mellitus can inhibit cytochrome P450 3A4, an enzyme responsible for the metabolism of nifedipine, used for the treatment of hypertension in pregnant women. We aimed to assess the effect of type 2 diabetes mellitus (T2DM) on the pharmacokinetics, placental transfer and distribution of nifedipine in amniotic fluid in hypertensive pregnant women. METHODS: The study was conducted in 12 hypertensive pregnant women [control group (CG)] and 10 hypertensive pregnant women with T2DM taking slow-release nifedipine (20 mg, 12/12 h). On the 34th week of gestation, serial blood samples were collected (0-12 h) after administration of the medication. At delivery, samples of maternal and fetal blood and amniotic fluid were collected for determination of nifedipine distribution in these compartments. RESULTS: The median pharmacokinetic parameters of CG were: peak plasma concentration (Cmax ) 26.41 ng ml-1 , time to reach Cmax (tmax ) 1.79 h, area under the plasma concentration vs. time curve from 0-12 h (AUC0-12 ) 235.99 ng.h ml-1 , half-life (t½) 4.34 h, volume of distribution divided by bioavailability (Vd/F) 560.96 l, and ClT /F 84.77 l h-1 . The parameters for T2DM group were: Cmax 23.52 ng ml-1 , tmax 1.48 h, AUC0-12 202.23 ng.h ml-1 , t½ 5.00 h, Vd/F 609.40 l, and apparent total clearance (ClT /F) 98.94 l h-1 . The ratios of plasma concentrations of nifedipine in the umbilical vein, intervillous space and amniotic fluid to those in the maternal vein for CG and T2DM were 0.53 and 0.44, 0.78 and 0.87, respectively, with an amniotic fluid/maternal plasma ratio of 0.05 for both groups. The ratios of plasma concentrations in the umbilical artery to those in the umbilical vein were 0.82 for CG and 0.88 for T2DM. CONCLUSIONS: There was no influence of T2DM on the pharmacokinetics or placental transfer of nifedipine in hypertensive women with controlled diabetes.

Analysis of nifedipine in human plasma and amniotic fluid by liquid chromatography-tandem mass spectrometry and its application to clinical pharmacokinetics in hypertensive pregnant women.

Nifedipine is a dihydropyridine calcium channel blocker used for the treatment of hypertension in pregnant women. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for analysis of nifedipine in human plasma and amniotic fluid. Separation of nifedipine and nitrendipine (IS) was performed using a LiChroCART(®) RP-Select B column and a mixture of water:acetonitrile:glacial acetic acid (30:70:0.5 v/v) as the mobile phase. Aliquots of 500µL of biological samples were extracted at pH 13 using dichloromethane:n-pentane (3:7 v/v). The validated method was applied to a study of the pharmacokinetics of nifedipine in human plasma and amniotic fluid samples collected up to 12h after administration of the last slow-release nifedipine (20mg/12h) dose to 12 hypertensive pregnant women. The estimated pharmacokinetic parameters of nifedipine showed a mean AUC(0-12) of 250.2ngh/mL, ClT/F of 89.2L/h, Vd/F of 600.0L and t1/2 5.1h. The mean amniotic fluid/plasma concentration ratio was 0.05. The methods proved to be highly sensitive by showing a lower quantification limit of 0.1ng/mL for both matrices. And this study reports for the first time the complete development and validation of the method to quantify nifedipine in amniotic fluid using LC-MS-MS.