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

Abstract

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 (C_max) 26.41 ng ml⁻¹, time to reach C_max (t_max) 1.79 h, area under the plasma concentration vs. time curve from 0–12 h (AUC_0–12) 235.99 ng.h ml⁻¹, half‐life (t½) 4.34 h, volume of distribution divided by bioavailability (Vd/F) 560.96 l, and Cl_T/F 84.77 l h⁻¹. The parameters for T2DM group were: C_max 23.52 ng ml⁻¹, t_max 1.48 h, AUC_0–12 202.23 ng.h ml⁻¹, t½ 5.00 h, Vd/F 609.40 l, and apparent total clearance (Cl_T/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.

What is Already Known About this Subject

• Nifidipine is a drug used for the treatment of hypertension during pregnancy.

• Hypertension is one of the most common complications occurring during pregnancy.

• The worldwide prevalence of diabetes has increased.

What this Study Adds

• Pharmacokinetic parameters of nifedipine in hypertensive pregnant women with and without T2DM taking 20 mg nifedipine retard every 12 h.

• Placental transfer of nifedipine was less than 60% and its distribution in amniotic fluid is about 5%.

• Controlled T2DM does not influence the pharmacokinetics of nifedipine in hypertensive pregnant women.

Tables of Links

TARGETS
Enzymes
CYP3A4

LIGANDS
Nifedipine

These Tables list key protein targets and ligands in this article that are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 1, and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 2.

Introduction

Nifedipine [(dimethyl 1,4‐dihydro‐2,6‐dimethyl‐4(2‐nitrophenyl)‐3,5pyridine‐decarboxylate] is a dihydropyridine calcium channel antagonist 3 used for the treatment of precordial angina, hypertension and other vascular diseases 4. Studies have demonstrated that it is an effective and safe drug for the treatment of hypertension during pregnancy as it reduces maternal arterial pressure without compromising the uteroplacental blood flow 5, 6.

Nifedipine is a highly apolar photosensitive compound which is fully absorbed in the gastrointestinal tract, predominantly from the jejunum, but its bioavailability is very low (approximately 45%) when the drug is administered by the oral route due to its significant presystemic metabolism. The drug is classified as a medication of intermediate and high hepatic extraction, undergoing intense cytochrome P450 (CYP) 3A4‐dependent metabolism. Only traces of nifedipine in its unchanged form are found in the urine (about 0.1%) 7, 8, 9, 10, 11, 12. More than 95% of this agent is highly bound to plasma proteins, although its systemic elimination does not depend on the protein‐bound fraction in the plasma owing to its hepatic elimination 13.

During pregnancy, the activity of CYP2A6, CYP2C9, CYP2D6, CYP3A4 and uridine diphosphate glucuronosyltransferase (UGT) is increased, while the activity of CYP1A2 and CYP2C19 is reduced. Some physiological changes, more evident during the third trimester, occur in the cardiovascular, renal, gastrointestinal and endocrine systems, and may alter the pharmacokinetics and pharmacodynamics of drugs. As a result of these changes, the dosage of medications is often modified in order to prevent adverse effects and inefficacy 11, 14, 15.

Diabetes mellitus can also alter the pharmacokinetics and metabolism of drugs 16, and some studies have demonstrated that it can change the activity of enzymes such as cytochrome P450 17, 18. A clinical study conducted by our group suggested that type 2 diabetes mellitus (T2DM) can alter the pharmacokinetics of nisoldipine, another dihydropyridine calcium channel antagonist, owing to a lower activity of CYP3A4 in nonpregnant hypertensive patients 19. Other clinical studies described that diabetes mellitus may inhibit or induce isoforms of cytochrome P450 17, 20, 21.

Given that pregnancy can induce and diabetes can inhibit CYP3A4, which is responsible for metabolizing nifedipine, there is a need for pharmacokinetic studies in pregnant women. The objective of the present study was therefore to assess the influence of T2DM on the drug's pharmacokinetics, placental transfer and distribution in amniotic fluid. These findings could help in deciding the treatment of choice for hypertension in pregnant women with T2DM.

Methods

The study was approved by the Institutional Review Board of the Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP‐USP) (Protocol no. 14421/2012) and all patients included in the study signed an informed consent to participate.

The power calculation for the pharmacokinetic study was carried out before the study. This was obtained using the Power and Sample Size software, version 2.1.31 (Vanderbilt University, Nashville, TN, USA) and the pharmacokinetic parameters of nifedipine for 20 healthy male volunteers treated with a single 10 mg dose of the drug 22. The study power was fixed at 80%, type I error at 5%, the standard deviation within the group at 99.4 ng.h ml⁻¹ and the difference between the mean area under the plasma concentration vs. time curve (AUC) values for the two groups at 40% of 281.2 ng.h ml⁻¹ (112.5 ng.h ml⁻¹). It was found that at least 10 volunteers per group would be necessary for the study.

Twelve hypertensive pregnant women [control group (CG)] and 10 hypertensive pregnant women with T2DM (T2DM group) taking 20 mg slow‐release nifedipine retard every 12 h for at least 2 weeks were included in the study. The patients from the T2DM group received treatment with insulin and metformin to maintain control of glycaemia levels. All patients were receiving prenatal care at the high‐risk pregnancy outpatient clinic of the Department of Gynecology and Obstetrics, HCFMRP–USP.

Patient characteristics

The following data were collected for each patient: age, body mass index (BMI), gestational age (GA) at the time of sample collection for pharmacokinetic analysis, GA on the day of delivery and medications used. Data collection on clinical follow‐up also took place, including blood pressure control and glycaemic levels. Data regarding GA at delivery, as well as newborn weight, length and Apgar score, were also obtained.

Clinical protocol

The study was conducted in two stages – the pharmacokinetic stage (stage 1) and the placental transfer stage (stage 2). The first stage began in the third trimester, starting in the 34th week of gestation. The patients were admitted to the Clinical Research Unit of HCFMRP‐USP after a 12 h fasting period, and breakfast was served 2 h after the administration of 20 mg slow‐release nifedipine; all medications were from the same batch.

A 5 ml sample of maternal blood was collected by a single puncture of a peripheral vein for the assessment of renal and hepatic function. For the analysis of plasma nifedipine concentrations, serial 10 ml samples of maternal blood were collected during the dose interval at 0, 10, 20, 30, 60, 90, 120, 150, 180, 240, 300, 360, 420, 480, 540, 600, 660 and 720 min.

The second stage started at the delivery, when the patients had been admitted to the maternity unit of HCFMRP/USP, with a simultaneous collection of 10 ml maternal blood, venous blood and arterial blood from the umbilical cord, blood from the intervillous space and an aliquot of amniotic fluid in order to assess the placental transfer and distribution of nifedipine in these compartments. Blood was collected from the umbilical cord only after the cord had been clamped and sectioned, and the placenta expelled, with no risk to mother or neonate. Blood samples were collected from the umbilical artery and vein, and from the intervillous space, according to the technique described by Camelo Júnior et al. 23.

During the Caesarean section, after the hysterotomy, the amniotic cavity was identified to enable the puncture to collect amniotic fluid, avoiding contamination of the latter with material of maternal origin. In vaginal delivery, the puncture was performed after identification of the amniotic sac, which was externalized through the external orifice of the cervix, using an epidural needle with a blunt tip, aspirating 10 ml amniotic fluid. All of these procedures were performed by previously trained medical staff who could guarantee that these materials would not reach fetal and/or placental tissue.

The blood and amniotic fluid samples were centrifuged at 1800 g for 15 min at 4°C and the plasma and amniotic fluid supernatants were collected, placed in cryogenic tubes and stored frozen at −70°C until analysis. The sampling was prepared under a sodium lamp and all tubes were wrapped in aluminium foil to prevent photodecomposition of nifedipine.

Determination of nifedipine in plasma and amniotic fluid

Nifedipine concentrations in the plasma and amniotic fluid were determined by liquid chromatography–tandem mass spectrometry (LC–MS/MS) using a method developed and validated by our group, as described in a previous study 24. The development and validation were conducted under a sodium lamp owing to the photolability of nifedipine and nitrendipine [internal standard (IS)].

Aliquots of 500 μl of plasma and amniotic fluid were spiked with 25 μl of the IS solution (nitrendipine, 50 ng ml⁻¹), alkalinized with 100 μl of 1 M sodium hydroxide, pH 13.0, and extracted with 5 ml of a mixture of pentane : dichloromethane (7:3). The tubes were shaken for 30 min and centrifuged at 1800 g for 10 min at 4°C. The organic phase (4 ml) was separated, transferred to conical glass tubes and evaporated dry in a vacuum sample concentrator. The residues were reconstituted with 100 μl of the mobile phase and 70 μl were injected into a reverse‐phase LiChroCART® RP‐Select B column (LiChrospher®, Merck, Darmstadt, Germany; 4 × 125 mm, particle size of 5 μm). The mobile phase consisted of a mixture of acetonitrile : water (70:30 v/v) acidified with 0.5% acetic acid at a flow rate of 1.0 ml min⁻¹. Protonated ions [M + H]⁺ and their respective ion products were monitored in the 347 > 315 m/z transition for nifedipine and in 361 > 315 m/z transition for IS.

The analytical curves built in the concentration ranges 0.1–100 ng ml⁻¹ plasma and 0.110 ng ml⁻¹ amniotic fluid were linear. No matrix effect was observed for the two matrices; the coefficients of variation for intra‐ and interassay precision, and the standard error of intra‐ and interassay accuracy were less than 15%.

Pharmacokinetic analysis

The pharmacokinetic analysis of nifedipine was carried out using the WinNonlin software, version 4.0 (Pharsight Corp, Mountain View, CA, USA). The pharmacokinetic parameters were calculated based on the plasma concentration vs. time curves assessed in the state of equilibrium during the 12 h dose interval. These data were obtained considering a monocompartmental model with first‐order kinetics and without lag time.

The AUC for the state of equilibrium was determined during the 12 h interval of nifedipine administration using the trapezoidal method. The apparent total clearance (Cl_T/F) was calculated using the equation Cl_T/F = Dose/AUC from 0–12 h (AUC_0–12). The apparent volume of distribution (Vd/F) was determined using the standard equation of the software. Peak plasma concentration (C_max) and the time to reach it (t_max) were directly determined from the plasma concentration values.

Statistical analysis

Continuous variables were calculated, and the median, 25th and 75th percentiles were displayed The Mann–Whitney test for unpaired data was used to compare the data between the control and diabetic groups of pregnant women, with a significance level of 5%. Data were analysed using the GraphPad Software, Inc. CA, USA.

Results

All women (n = 22) were divided into two groups – CG, consisting of 12 hypertensive women, and the study group (T2DM), consisting of 10 hypertensive women with T2DM. The baseline characteristics (demographic and clinical data) of the pregnant women investigated are displayed in Table 1 by medians, 25th and 75th percentiles.

Table 1.

Characteristics of women included in the study, in the control and T2DM groups. Data are reported as median (25th and 75th percentiles)

	Groups
Parameters	Control (n = 12) Median (25th–75th percentiles)	T2DM (n = 10) Median (25th–75th percentiles)	P‐value
Age (years)	32 (25–36)	37 (33–41)	0.04a
BMI (kg m−2)	39.1 (37.3–43.8)	40.9 (35.5–44.7)	0.92
GA during collection (weeks)	35.3 (34.9–37.1)	34.8 (34.2–36.2)	0.20
GA on the day of delivery (weeks)	39.1 (38.7–39.5)	36.9 (35.2–38.4)	0.02a

BMI, body mass index; GA, gestational age; T2DM, type 2 diabetes mellitus

^aMann–Whitney test, P‐value <0.05

Five patients were taking methyldopa combined with nifedipine in the CG group and eight patients were taking methyldopa combined with nifedipine in the T2DM group. No patients had to increase the dosage of medication or had preeclampsia. In the CG group, all patients were taking folic acid and ferrous sulphate, and three were taking acetylsalicylic acid. In the T2DM group, seven patients were taking folic acid, ferrous sulphate and metformin, nine patients were using NPH insulin, five were using regular insulin and one patient was taking betamethasone. In the CG group, five patients had a vaginal delivery and seven underwent a Caesarean section; five patients successfully induced birth labour, two failed the labour induction and had a Caesarean section; three had Caesarean section because of two or more previous Caesarean sections and two underwent surgery because of fetal distress. In the T2DM group, three patients had a vaginal delivery and seven had Caesarean sections; three patients induced labour, two failed the induction and had a Caesarean section; one had a Caesarean delivery because of two or more previous Caesarean sections, three because of fetal distress and one because of absolute oligoamnios.

During the 12 h of admission at the Clinical Research Unit of HCFMRP‐USP, all patients were submitted to cardiotocography for fetal heart rate monitoring and uterine contractility. All fetuses were found to be active and reactive. The haemodynamic parameters for all women were monitored by recording systolic and diastolic blood pressure every 4 h. All patients were haemodynamically stable throughout the study. Figure 1 presents the plasma concentration of slow‐release nifedipine (on a logarithmic scale) as a function of time compared with the course of mean arterial pressure (MAP, mmHg) for the CG and T2DM subjects. It was possible to observe a maximum fall in MAP during the measurement following the maximum plasma concentration and its return to MAP values over a 12 h period similar to the values for time zero, demonstrating the action of the drug during the dose interval used, as well as its efficacy.

Figure 1.

Plasma concentration and mean arterial pressure (AP) vs. time in hypertensive pregnant women in the CG (n = 12) and T2DM (n = 10) groups after administration of multi‐dose 20 mg of slow‐release nifedipine, 20 mg/12 h. Data are reported as median. Calculation of mean AP: [(Systolic AP) + 2 × (Diastolic AP)]/3

All diabetic patients had already been diagnosed with T2DM before pregnancy. Their median value (25th to 75th percentiles) of fasting glycaemia was 81 mg dl^–1 (70.5–116) and their median value of glycated haemoglobin was 6.35% (6.13–6.88).

Laboratory tests were carried out in order to assess the functional normality of the haematological/renal, hepatic and endocrine systems. The results obtained were considered to be within normal limits. All pregnant women had negative serologies for human immunodeficiency virus, hepatitis B and hepatitis C, syphilis, toxoplasmosis and rubella.

Resolution of pregnancy occurred according to an obstetric indication. All newborns (NB) of CG mothers had 1st and 5th min Apgar scores of 7 or more, characterizing well‐being at birth. Only 3% of NB of T2DM patients had a 1st min Apgar score of less than 7 and only 1% had a 5th min Apgar score of less than 7. No diseases or major congenital malformations were diagnosed in NB at birth and no adverse effects attributable to the use of nifedipine during pregnancy were observed. All NB progressed favourably during the postnatal period. Median weight and height at birth were 3330 g and 48.5 cm, respectively, for CG NB and 3010 g and 47.25 cm for T2DM NB. Four NB from the T2DM group had low birth weight and prematurity (40%). The abnormalities of the placenta showed no relevant macroscopic changes.

The median curves for plasma nifedipine concentration (ng ml⁻¹) vs. time (h) for the two groups were determined during the 12 h dose interval using the monocompartmental model (Figure 1). The pharmacokinetic parameters (medians and 25th and 75th percentiles) were analysed using the Mann–Whitney test, with no significant difference between groups (Table 2).

Table 2.

Pharmacokinetic parameters of nifedipine in hypertensive pregnant women in the control and T2DM groups. Data are reported as median (25th and 75th percentiles)

	Groups
	Control (n = 12)	T2DM (n = 10)
Parameters	Median (25th–75th percentiles)	Median (25th–75th percentiles)	P
Cmax (ng ml−1)	26.41 (23.98–29.88)	23.52 (21.21–27.87)	0.23
tmax (h)	1.79 (1.24–1.96)	1.48 (1.03–1.73)	0.46
AUC0–12 (ng.h ml−1)	235.99 (203.72–261.97.28)	202.23 (185.54–235.52)	0.38
Kel (h−1)	0.16 (0.15–0.18)	0.14 (0.13–0.25)	0.72
t½ (h)	4.34 (3.87–4.64)	5.00 (4.45–5.84)	0.28
Vd/F (l)	560.96 (506.85–720.31)	609.40 (357.28–742.05)	0.87
ClT/F (l h−1)	84.77 (76.37–98.24)	98.94 (85.14–107.79)	0.38

AUC_0–12, area under the plasma concentration vs. time curve from time zero to 12 h; Cl_T/F, apparent total clearance; C_max, peak concentration; Kel, elimination rate constant; t_max, time to reach maximum concentration; t_½, elimination half‐life; T2DM, type 2 diabetes mellitus; Vd/F: apparent volume of distribution. Mann–Whitney test for paired data, P < 0.05

Table 3 lists the data for placental transfer, expressed as the ratio of the nifedipine concentration in the umbilical vein to that in the maternal vein; in the intervillous space to that in the maternal vein; and in the umbilical artery to that in the umbilical vein for the two groups. Data are reported as median, 25th and 75th percentiles. No statistically significant differences were seen between groups.

Table 3.

Placental transfer of nifedipine and distribution of the drug in the amniotic fluid in the control and T2DM groups. Data are reported as median (25th and 75th percentiles)

	Groups
	Control (n = 12)	T2DM (n = 10)
Samples (ratio)	Median (25th–75th Percentiles)	Median (25th–75th Percentiles)	P
Umbilical vein/maternal vein	0.53 (0.35–0.74)	0.44 (0.36–0.56)	0.50
Intervillous space/maternal vein	0.78 (0.62–0.99)	0.87 (0.63–0.92)	0.97
Umbilical artery/umbilical vein	0.82 (0.66–1.18)	0.88 (0.48–1.12)	0.67
Amniotic fluid/maternal vein	0.05 (0.02–0.08)	0.05 (0.04–0.08)a	0.79

T2DM, type 2 diabetes mellitus;

^a n = 8. Mann‐Whitney test for paired data, P < 0.05.

Figure 2 represents the median of nifedipine concentrations in maternal and fetal compartments during delivery. We observed a 50% ratio in feto‐maternal concentration, an 80% ratio in intervillous space/mother and a 90% ratio in fetal umbilical artery/vein, showing a transfer ratio of 0.5 and a equilibrium between the intervillous space and maternal vessel, with a ratio of 0.8. The fact that the ratio between the fetal umbilical artery and vein was close to 1 demonstrates a low rate of fetal drug metabolism. With regard to the concentration of amniotic fluid/maternal plasma, we observed a 5% ratio in the distribution of nifedipine, reflecting a low excretion of the drug into the amniotic fluid. No significant differences were observed for any fetal/maternal relationships described either group.

Figure 2.

Ratio of nifedipine concentrations in fetal and maternal compartments at delivery. Data are reported as medians

Discussion

The pharmacokinetics of nifedipine, determined by C_max, t_max, AUC_0–12, Cl_T/F, Vd/F and half‐life (t½), did not differ significantly between the two groups. With regard to the maternal and fetal compartment analysis, the ratios of nifedipine concentration in these compartments did not differ significantly between the groups, demonstrating that T2DM does not influence the placental transfer of the drug.

The comparison between pregnant women from the present study with healthy volunteers treated with different nifedipine doses revealed a reduction in C_max and t½ 9, 22, 25, which was probably due to an increase in the clearance of the drug.

Although the present patients were being treated with multiple doses of 20 mg slow‐release nifedipine, the t_max of the pregnant patients was comparable to that of healthy volunteers treated with a single dose of 20 mg slow‐release nifedipine 9. This demonstrated that the value was unchanged in a multiple‐dose regimen and during pregnancy, probably due to the slow‐release formulation of the drug.

Nifedipine is a drug of intermediate and high hepatic extraction 7, 8 and, according to Anderson 11, during pregnancy there is an increase in hepatic flow, with a subsequent increase in the clearance of, and a reduction in the AUC for, drugs with a high rate of hepatic extraction. This may explain the reduced AUC in hypertensive patients compared with healthy volunteers treated with a single 20 mg dose of slow‐release nifedipine 9.

The T2DM patients were appropriately medicated in order to achieve adequate glycaemic levels throughout pregnancy; in general, they had normal glycaemia, and glycated haemoglobin values below the expected values that would indicate decompensated diabetes mellitus 26.

Diabetes mellitus can cause conformational changes in the structure of albumin, complicating the binding of drugs and resulting in an increase in the free fraction 17. The importance of hyperglycaemia for CYP activity has been shown to be due to total CYP content as the activity of hepatic CYP1A and CYP3A correlates with blood glucose levels in rats with experimental diabetes 27. The extent of diabetic complications depends on the control of glycaemia and the duration of diagnosis of the disease 28.

A multinational epidemiological study showed that the risk of adverse maternal, fetal and neonatal outcomes increased depending on the increase in maternal glycaemia 29. Given that these patients were under appropriate clinical care in order to reach adequate glycaemic levels throughout gestation, no significant differences were detected between the groups. Thus, these results suggest that well‐controlled T2DM has no influence on the pharmacokinetics of nifedipine in hypertensive pregnant women. A previous study by our group 30 also found no influence of T2DM on the pharmacokinetics of metformin in obese pregnant women with appropriate glycaemic control.

The age of the women in the T2DM group was significantly older than that in the CG group. However, a study conducted by Kleinbloesem et al. 13 showed that age does not influence the activity of CYP3A4, which is responsible for the metabolism of nifedipine.

Most patients were considered to be obese, with a median weight of 39.1 kg m⁻² and 40.9 kg m⁻² for CG and T2DM women, respectively. Obesity can modify the pharmacokinetics of drugs owing to fatty liver infiltration, causing alterations in the CYP enzymes, and possibly changing the volume of distribution and drug clearance 31, 32, 33. However, no changes related to body fat were detected in the antihypertensive effect of nifedipine 34 and no statistically significant differences in BMI were observed between groups. Despite the difference in gestational ages, women from both groups delivered after 37 weeks of gestation. A study by Marin et al. 35 found no correlation between nifedipine serum levels and BMI, as well as gestational age. They demonstrated that it is not necessary to adjust the nifedipine dose in obese patients and among different gestational ages.

The placental transfer of nifedipine was about 50% in both groups, which means that higher nifedipine doses should be administered with caution, in order to avoid effects on the fetus. High nifedipine concentrations may cause fetal hypotension 36. The risk of drug transfer to the fetus may be direct, depending on the quantity of drug transferred through the placenta, or indirect, causing a change in placental function 37. Few studies have been conducted on the placental transfer of nifedipine.

The reported data are related to the use of nifedipine as a tocolytic agent with different doses. Studies have reported a 77% transfer rate of gastrointestinally released nifedipine (30–150 mg day^–1), a 76% transfer rate in normotensive women prepared for Caesarean delivery (a single sublingual 20 mg tablet) and a 72% transfer rate for nifedipine capsules (20 mg 6/6 h) 38, 39, 40.

The ratios of nifedipine concentration in the intervillous space to that in the maternal vein were 0.78 for CG and 0.87 for T2DM subjects, with equilibrium being observed between these collection sites. We have previously detected that concentration ratios for lidocaine in normal pregnant women were 1.01 and for diabetic pregnant women were 0.88 41. These findings corroborate that the intervillous space is a continuous region of the maternal vein, which may be considered as a single compartment.

Fetal metabolism was assessed using the ratio of the nifedipine concentration in the umbilical artery to that in the umbilical vein. The ratios were 0.82 for CG and 0.88 for T2DM women. These maternal/fetal ratios demonstrate a low metabolic rate in the fetus, probably due to a relative hepatic immaturity in this phase of development. They may also be related to the low expression of CYP3A4 in the fetal liver, responsible for the metabolism of nifedipine 42.

Nifedipine was detected in all amniotic fluid samples, with an amniotic fluid/maternal plasma ratio of 0.05 for both groups. Given that more than 95% of nifedipine is bound to plasma proteins, it is possible to explain the low concentrations observed in the amniotic fluid 43.

In the third trimester, amniotic fluid is produced by fetal urine rather than transudate. Considering that the fetus swallows 210–760 ml day^–1 of amniotic fluid, if the fluid contains high concentrations of the drug, this may represent continuous fetal exposure to the drug administered to the mother 44. In the present study, low nifedipine concentrations were detected in the amniotic fluid, representing a low fetal exposure to the drug.

The present study of the pharmacokinetics and placental transfer of nifedipine in pregnant women is important because only 1.29% of the clinical pharmacokinetic studies indexed in PubMed reported data for pregnant women, according to a review by McCormack and Best 45. These authors also stated that the understanding of the clinical pharmacology of medications during pregnancy is of fundamental importance for the development of ideal dosage regimens. Inappropriate drug dosages during pregnancy may have adverse consequences for both mother and fetus.

The present study revealed relevant data about the pharmacokinetic parameters, placental transfer and distribution in amniotic fluid of nifedipine in hypertensive pregnant women with and without T2DM, taking 20 mg nifedipine retard every 12 h. The extent of the placental transfer of nifedipine is important; if it is less than 60%, its distribution in the amniotic fluid is low, at about 5%; the AUC_0–12 values obtained in the present study agree with the target values relating to the efficacy of the medication.

Controlled T2DM does not influence the pharmacokinetics and placental transfer of nifedipine in hypertensive pregnant women. These data indicate the need for further studies that might identify the influence of T2DM on patients with uncontrolled glycaemia who do not receive the appropriate medical care.

Competing Interests

There are no competing interests to declare.

The authors would like to thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ) , grants 133 301/2013–3 and 471 475/2014–0, and o Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FAEPA ) for financial support.

Filgueira, G. C. O. , Filgueira, O. A. S. , Carvalho, D. M. , Marques, M. P. , Moisés, E. C. D. , Duarte, G. , Lanchote, V. L. , and Cavalli, R. C. (2017) Effect of type 2 diabetes mellitus on the pharmacokinetics and transplacental transfer of nifedipine in hypertensive pregnant women. Br J Clin Pharmacol, 83: 1571–1579. doi: 10.1111/bcp.13226.