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This study investigates the influence of pregnancy on the in vivo activity of the intestinal P‐glycoprotein (P‐gp) and hepatic organic anion transporters polypeptide (OATP/BCRP) using, respectively, fexofenadine and rosuvastatin as probe drugs. Eleven healthy participants were investigated during the third trimester of pregnancy (Phase 1, 28 to 38 weeks of gestation) and in the postpartum period (Phase 2, 8 to 12 weeks postpartum). In both phases, after administration of a single oral dose of fexofenadine (60 mg) and rosuvastatin (5 mg), serial blood samples were collected for up to 24 h. Rosuvastatin and fexofenadine in plasma were analyzed by LC‐MS/MS using previously validated methods. The pharmacokinetic parameters of fexofenadine and rosuvastatin (Phoenix WinNonLin software) with normal distribution (Shapiro–Wilk test) are presented as geometric mean and 90% confidence interval. Phases 1 and 2 were compared using the t test (P < .05). Fexofexadine AUC0‐24 values do not differ (P‐value: .0715) between Phase 1 (641.9 ng h/mL [500.6‐823.1]) and Phase 2 (823.8 ng h/mL [641.5‐1057.6]) showing that pregnancy (third trimester) does not alter intestinal P‐gp activity. However, rosuvastatin AUC0‐24 values are higher (P‐value: .00005) in Phase 1 (18.7 ng h/mL [13.3‐26.4]) when compared to Phase 2 (9.5 ng h/mL [6.7‐13.4]), suggesting inhibition of OATP1B1/OATP1B3 transporters. In conclusion, pregnancy assessed during the third trimester does not alter the intestinal P‐gp activity but reduces the activity of hepatic OATP1B1/OATP1B3 transporters. Therefore, adjustments in dosage regimens may be necessary for drugs with low therapeutic index, substrates of the OATP1B1/OATP1B3 transporters, administered during the third trimester of pregnancy. [ABSTRACT FROM AUTHOR]

This work aimed to evaluate the total, unbound, renal, and hepatic clearances of raltegravir (RAL) and the formation and elimination clearances of raltegravir glucuronide (RAL GLU) in pregnant women living with HIV. The participants received RAL 400 mg twice daily during the third trimester (n = 15) of gestation, delivery (n = 15), and the postpartum period (n = 8). Pharmacokinetic parameter values were calculated on the basis of plasma and urine data using noncompartmental methods. RAL clearances for the third trimester of gestation were as follows: total clearance: geometric mean, 63.63 L/h (95% CI, 47.5–85.25); renal clearance: geometric mean, 2.56 L/h (95% CI, 1.96–3.34); hepatic clearance: geometric mean, 60.52 L/h (95% CI, 44.65–82.04); and unbound clearance: geometric mean, 281.14 L/h (95% CI, 203.68–388.05). RAL GLU formation and elimination clearances for the third trimester of gestation were 7.57 L/h (95% CI, 4.94–11.6) and 8.71 L/h (95% CI, 6.71‐11.32), respectively. No differences were observed in RAL GLU pharmacokinetic parameters between the third trimester of gestation and the postpartum period, except for higher formation (7.57 vs 4.03 L/h) and elimination (8.71 vs 4.92 L/h) clearances during the third trimester. The findings based on plasma and urine data are consistent with an increase in the hepatic uridine 5′ diphospho‐glucuronosyltransferase isoenzymes activities involved in RAL metabolism during pregnancy, and the formation of RAL GLU is a minor route of RAL elimination. Compared to the postpartum period, in the third trimester of gestation, the similar RAL plasma exposure in pregnant women reinforces the maintenance of an RAL regimen including a 400‐mg oral dose twice daily during pregnancy. [ABSTRACT FROM AUTHOR]

Aim: No study has evaluated the betamethasone pharmacokinetics in twin pregnancies according to chorionicity. This study aimed to describe and compare the betamethasone pharmacokinetic parameters in singleton and dichorionic (DC) and monochorionic twin pregnancies in the third trimester of pregnancy. Methods: Twenty‐six pregnant women received 2 intramuscular doses of 6 mg of betamethasone sodium phosphate plus 6 mg betamethasone acetate due to preterm labour. Serial blood samples were collected for 24 hours after the first intramuscular dose of betamethasone esters. Betamethasone plasma concentrations were quantified using a validated liquid chromatography–tandem mass spectrometry analytical method, and the pharmacokinetic parameters were obtained employing a noncompartmental model. Preliminary data on the betamethasone placental transfer are also presented. Results: The geometric mean (95% confidence interval) of AUC0‐∞ 645.1 (504.3–825.2) vs. 409.8 (311.2–539.6) ng.h/mL and CL/F 17.70 (13.84–22.65) vs. 27.87 (21.17–36.69) were significantly different, respectively, in singleton pregnancies when compared to DC twins. Conclusion: Data from this study suggest that the presence of 2 foetoplacental units may increase the betamethasone metabolism by hepatic CYP3A4 and/or placental 11β‐HSD2 enzymes. Pharmacokinetic–pharmacodynamic clinical studies are needed to investigate whether these betamethasone pharmacokinetic changes have clinical repercussions for the newborns and require dose adjustment in DC twin pregnancies. [ABSTRACT FROM AUTHOR]

Bupivacaine, a local anesthetic, is commercialized as a racemic mixture of R-bupivacaine and S-bupivacaine enantiomers. HIV infection increases the expression of placental P-glycoprotein (P-gp), and antiretroviral (ARV) therapy inhibits cytochrome P450 3A and P-gp. The present study evaluates the kinetic disposition of bupivacaine enantiomers in HIV-infected parturient women on ARV therapy. In this study, HIV-infected parturient women (n = 10) treated with zidovudine, lamivudine, lopinavir, and ritonavir were investigated. Anesthesia and/or analgesia was achieved by the administration of 0.5% racemic bupivacaine hydrochloride with 1:200000 epinephrine in the epidural space at doses of 2.5 to 22.5 mg. Maternal serial blood samples were obtained at the time immediately before and 5, 15, 30, 45, and 60 minutes and 2, 4, 6, 8, 10, 12, and 14 hours after administration of the bupivacaine. At the time of delivery, samples of maternal and umbilical cord vein blood were also collected. The results suggest that bupivacaine pharmacokinetics are enantioselective, revealing higher maternal plasma concentrations of the R-bupivacaine enantiomer (area under the total plasma concentration-time curve was calculated by the trapezoid method with extrapolation to infinity/dose(S)/(R) = 0.91; P < .05). The plasma unbound fraction of the drug (0.09 vs 0.06) and the umbilical cord vein/maternal plasma ratio (0.47 vs 0.39) were higher for the R-bupivacaine enantiomer than the S-bupivacaine enantiomer (P < .05). ARV therapy with ritonavir confers an enantioselective interaction between the enantiomers of bupivacaine and placental P-gp, producing greater inhibition of efflux transport of the R-bupivacaine enantiomer. Possible changes in the well-being of the fetuses of mothers under analgesia may be a consequence of the increased placental transfer of bupivacaine enantiomers to the fetal circulation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Neonatal effects of drugs administered to mothers before delivery depend on the quantity that crosses the placental barrier, which is determined by the pharmacokinetics of the drug in the mother, fetus, and placenta. Diabetes mellitus can alter the kinetic disposition and the metabolism of drugs. This study investigated the placental transfer of lidocaine and its metabolite monoethylglycinexylidide (MEGX) in pregnant women with gestational diabetes mellitus (GDM) submitted to peridural anesthesia. Patients and Methods: A total of 10 normal pregnant women (group 1) and 6 pregnant women with GDM (group 2) were studied, all at term. The patients received 200 mg 2% lidocaine hydrochloride by the peridural locoregional route. Maternal blood samples were collected at the time of delivery and, after placental expulsion, blood samples were collected from the intervillous space, umbilical artery, and vein for determination of lidocaine and MEGX concentrations and analysis of the placental transfer of the drug. Results: The following respective lidocaine ratios between the maternal and the fetal compartments were obtained for groups 1 and 2: umbilical vein/maternal peripheral blood, 0.60 and 0.46; intervillous space/maternal blood, 1.01 and 0.88; umbilical artery/umbilical vein, 0.77 and 0.91; and umbilical vein/intervillous space, 0.53 and 0.51. The following MEGX ratios for groups 1 and 2 were, respectively, fetal/maternal, 0.43 and 0.97; intervillous space/maternal blood, 0.64 and 0.90; umbilical artery/umbilical vein, 1.09 and 0.99; and umbilical vein/intervillous space, 0.55 and 0.78. Conclusion: Gestational diabetes mellitus did not affect the transplacental transfer of lidocaine but interfered with the transfer of MEGX, acting as a mechanism facilitating the transport of the metabolite. [ABSTRACT FROM AUTHOR]

Clinical experience shows an increased duration of labor in obese parturient women. It is unclear if this population should receive the same dose of vaginal misoprostol for induction of labor as non‐obese parturient women. We investigate the influence of obesity on the pharmacokinetics and placental transfer of the metabolite misoprostol acid in parturient women. Parturient women (n = 40) were enrolled and received misoprostol 25 µg/6 h vaginally and were allocated into two groups according to the pre‐pregnancy body mass index (BMI <30 kg/m2 non‐obese, n = 18 or BMI >30 kg/m2 obese, n = 22) or according to the labor induction outcome (failure [n = 10] or success [n = 30]). Blood collection for pharmacokinetic study occurred after the first misoprostol dose. The pharmacokinetic parameters obtained in non‐obese parturient women were not statistically different from those obtained in obese group (P Value >  .05). However, when the parturient women were grouped by the labor induction outcome, the failed labor induction group presented a higher (median [interquartile range]) BMI (44.4 [34.6‐47.9] vs 33.7 [28.9‐36.5] kg/m2) (P Value =  .0017), lower Cmax (11.5 [4.82‐22.2] vs 22.8 [14.2‐30.8] pg/mL) (P Value =  .0308) and not statistically different AUC0‐6 (31.8 [13.4‐61.5] vs 53.4 [35.4‐77.7]) pg·h/mL) (P Value =  .0580) and tmax (2.50 [1.19‐4.25] vs 3.00 (1.88‐5.00) h (P Value =  .3198) when compared with parturient women who presented successful labor induction. This data suggests a higher loading dose (higher volume of distribution) and unchanged maintenance dose (unchanged AUC0‐6) of misoprostol for this population. Further studies are required to investigate the efficacy and safety of higher misoprostol loading doses for this population. [ABSTRACT FROM AUTHOR]

• Validated methods for RAL and/or RAL GLU analysis in urine and plasma. • Application in a maternal-fetal pharmacokinetic study. • These methods can be applied in studies regarding to UGT1A1 activity on raltegravir disposition. Raltegravir (RAL) is a HIV-integrase inhibitor recommended for treatment of HIV type 1 infection during pregnancy. The elimination of RAL to RAL glucuronide (RAL GLU) is mediated primarily by UDP glucuronosyltransferase 1A1 (UGT1A1). The present study shows the development and validation of 4 different methods for the analysis of RAL and RAL GLU in plasma and in urine samples. The methods were applied to evaluate the maternal-fetal pharmacokinetics of RAL and RAL GLU in a HIV-infected pregnant woman receiving RAL 400 mg twice daily. The sample preparation for RAL and RAL GLU analysis in 25 μL plasma and 100 μL diluted urine (10-fold with water containing 0.1% formic acid) were carried out by protein precipitation procedure. RAL and RAL GLU generate similar product mass fragments and require separation in the chromatographic system, so a suitable resolution was achieved for unchanged RAL and RAL GLU employing Ascentis Express C18 (75 × 4.6 mm, 2.7 μm) for both plasma and urine samples. The methods showed linearities at the ranges of 0.1–13.5 μg/mL RAL and 0.15–19.5 μg/mL RAL GLU in urine and 10–2000 ng/mL RAL and 2.5–800 RAL GLU in plasma. Precise and accurate evaluation showed coefficients of variation and relative errors ≤ 15%. The methods have been successfully applied in a maternal-fetal pharmacokinetic study. [ABSTRACT FROM AUTHOR]

• The validation guidelines focus on analyses of exogenous compounds. • A background subtraction approach for C and 6β determination in urine. • Application in within day variability study in pregnancy and postpartum. Different methods have been used for CYP3A phenotyping, such as probe drugs or the urinary index 6β-hydroxycortisol/cortisol ratio (6β-OHF:C). This work describes a simple and affordable method for the simultaneous determination of the endogenous compounds cortisol and 6β-hydroxycortisol in urine using a background subtraction approach. The method was applied to investigate the CYP3A activity in HIV-infected pregnant women (n = 9) in the third trimester and postpartum periods. Also, the within-day variability in the 6β-OHF:C index was also evaluated. The sample preparation consists of a pre-cleanup with acetonitrile followed by liquid-liquid extraction with ethyl acetate. The analytes were resolved by employing an Acquity UPLC®BEH C18 column with a mobile phase that consisted of a mixture of acetonitrile containing 0.1% formic acid and 0.1% formic acid in gradient mode. The method presented linearities of 1–1.000 ng/mL and 2–1.000 ng/mL for C and 6β-OHF, respectively, and presented acceptable precision and accuracy. Qualitative and quantitative matrix effects tests were also performed. A high 6β-OHF:C within-day variability was observed in both phases. In the third trimester period, the 6β-OHF:C ranged from 2.57 to 51.69, with a mean ± standard deviation (SD) of 15.12 ± 5.41 (n = 9). Similar values were obtained in the postpartum period, with 6β-OHF:C ranging from 3.48 to 44.54 with a mean ± SD of 14.37 ± 5.73 (n = 7). Even though the 6β-OHF:C is a non-invasive index for CYP3A phenotyping, its use is susceptible to high within-day variability. [ABSTRACT FROM AUTHOR]

• A validated method for MA analysis in plasma with the lowest LLOQ. • Application in a maternal-fetal pharmacokinetic study. • Method applied in a study of low misoprostol dose of 25 μg administered vaginally. • First report of MA PK following misoprostol 25 μg administered vaginally. • MA showed high placental transfer with accumulation in the fetal compartment. Misoprostol is a prostaglandin E1 synthetic analogous used for elective interruptions of early pregnancy, treatment of incomplete abortion, postpartum hemorrhage and induction of full-term labor. Its a lipophilic drug, passing by extensive and rapid pre-systemic metabolism into the active metabolite, misoprostol acid (MA). The objective of this study was to develop and validate a highly sensitive method for MA determination in plasma using UPLC-MSMS, with application in a study of maternal-fetal pharmacokinetics in healthy parturients women (n = 10) after administration of 25 μg misoprostol vaginally. The method presented linearity of 2−10 pg/mL and acceptable precision, accuracy, plasma and solution stability. The parturients women presented median (interquartile range) values of AUC0−6 of 68.0 (40.8–84.7) pg.h/mL, C max of 21.9 (11.9–30.1) pg/mL and T max of 2.25 (0.69–5.00) h. The placental transfer of MA was assessed from the umbilical vein/maternal blood ratios of 1.40 (0.91–2.13) and intervillous space/maternal blood ratios of 0.49 (0.15–3.41). In conclusion, this method presented high sensitivity, being able to quantify MA in plasma samples following a low 25 μg misoprostol administered vaginally aimed to induce labor in parturients women. Additionally, this is the first description of the placental transfer of MA after a vaginal administration of misoprostol. [ABSTRACT FROM AUTHOR]