N
-methylnicotinamide (1-NMN) has been investigated as an endogenous probe for the renal transporter activity of organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins 1 and ...2-K (MATE1 and MATE2-K). As pregnancy increased the renal secretion of metformin, a substrate for OCT2, MATE1, and MATE2-K, we hypothesized that the renal secretion of 1-NMN would be similarly affected. Blood and urine samples collected from women prescribed metformin for type 2 diabetes, gestational diabetes, and polycystic ovarian syndrome during early, mid, and late pregnancy (
= 34 visits) and postpartum (
= 14 visits) were analyzed for 1-NMN using liquid chromatography-mass spectrometry. The renal clearance and secretion clearance, using creatinine clearance to correct for glomerular filtration, were estimated for 1-NMN and correlated with metformin renal clearance. 1-NMN renal clearance was higher in both mid (504 ± 293 ml/min,
< 0.01) and late pregnancy (557 ± 305 ml/min,
< 0.01) compared with postpartum (240 ± 106 ml/min). The renal secretion of 1-NMN was 3.5-fold higher in mid pregnancy (269± 267,
< 0.05) and 4.5-fold higher in late pregnancy compared with postpartum (342 ± 283 versus 76 ± 92 ml/min,
< 0.01). Because creatinine is also a substrate of OCT2, MATE1, and MATE2-K, creatinine clearance likely overestimates filtration clearance, whereas the calculated 1-NMN secretion clearance is likely underestimated. Metformin renal clearance and 1-NMN renal clearance were positively correlated (r
= 0.68,
< 0.0001). 1-NMN renal clearance increases during pregnancy due to increased glomerular filtration and net secretion by renal transporters.
This study's primary objective was to fully characterize the pharmacokinetics of metformin in pregnant women with gestational diabetes mellitus (GDM) versus nonpregnant controls. Steady-state oral ...metformin pharmacokinetics in pregnant women with GDM receiving either metformin monotherapy (
= 24) or a combination with glyburide (
= 30) as well as in nonpregnant women with type 2 diabetes mellitus (T2DM) (
= 24) were determined utilizing noncompartmental techniques. Maternal and umbilical cord blood samples were collected at delivery from 38 women. With both 500- and 1000-mg doses, metformin bioavailability, volume of distribution beta (V
), clearance, and renal clearance were significantly increased during pregnancy. In addition, in the women receiving metformin 500 mg, significantly higher metformin apparent oral clearance (CL/F) (27%), weight-adjusted renal secretion clearance (64%), and apparent oral volume of distribution beta (V
/F) (33%) were seen during pregnancy. Creatinine clearance was significantly higher during pregnancy. Increasing metformin dose from 500 to 1000 mg orally twice daily significantly increased V
/F by 28%, weight-adjusted V
/F by 32% and CL/F by 25%, and weight-adjusted CL/F by 28% during pregnancy. Mean metformin umbilical cord arterial-to-venous plasma concentration ratio was 1.0 ± 0.1, venous umbilical cord-to-maternal concentration ratio was 1.4 ± 0.5, and arterial umbilical cord-to-maternal concentration ratio was 1.5 ± 0.5. Systemic exposure after a 500-mg dose of metformin was lower during pregnancy compared with the nonpregnant women with T2DM. However, in patients receiving metformin 1000 mg, changes in estimated bioavailability during pregnancy offset the changes in clearance leading to no significant change in CL/F with the higher dose. SIGNIFICANCE STATEMENT: Gestational diabetes mellitus complicates 5%-13% of pregnancies and is often treated with metformin. Pregnant women undergo physiological changes that alter drug disposition. Preliminary data suggest that pregnancy lowers metformin concentrations, potentially affecting efficacy and safety. This study definitively describes pregnancy's effects on metformin pharmacokinetics and expands the mechanistic understanding of pharmacokinetic changes across the dosage range. Here we report the nonlinearity of metformin pharmacokinetics and the increase in bioavailability, clearance, renal clearance, and volume of distribution during pregnancy.
Information on the pharmacokinetics of tacrolimus during pregnancy is limited to case reports despite the increasing number of pregnant women being prescribed tacrolimus for immunosuppression.
Blood, ...plasma, and urine samples were collected over 1 steady-state dosing interval from women treated with oral tacrolimus during early to late pregnancy (n = 10) and postpartum (n = 5). Total and unbound tacrolimus as well as metabolite concentrations in blood and plasma were assayed by a validated liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) method. A mixed-effect linear model was used for comparison across gestational age and using postpartum as the reference group.
The mean oral clearance (CL/F) based on whole-blood tacrolimus concentration was 39% higher during mid-pregnancy and late pregnancy compared with postpartum (47.4 ± 12.6 vs. 34.2 ± 14.8 L/h, P < 0.03). Tacrolimus-free fraction increased by 91% in plasma (f(P)) and by 100% in blood (f(B)) during pregnancy (P = 0.0007 and 0.002, respectively). Increased fP was inversely associated with serum albumin concentration (r = -0.7, P = 0.003), which decreased by 27% during pregnancy. Pregnancy-related changes in f(P) and f(B) contributed significantly to the observed gestational increase in tacrolimus whole-blood CL/F (r² = 0.36 and 0.47, respectively, P < 0.01). In addition, tacrolimus whole-blood CL/F was inversely correlated with both hematocrit and red blood cell counts, suggesting that binding of tacrolimus to erythrocytes restricts its availability for metabolism. Treating physicians increased tacrolimus dosages in study participants during pregnancy by an average of 45% to maintain tacrolimus whole-blood trough concentrations in the therapeutic range. This led to striking increases in unbound tacrolimus trough concentrations and unbound area under the concentration-time curve, by 112% and 173%, respectively, during pregnancy (P = 0.02 and 0.03, respectively).
Tacrolimus pharmacokinetics are altered during pregnancy. Dose adjustment to maintain whole-blood tacrolimus concentration in the usual therapeutic range during pregnancy increases circulating free drug concentrations, which may impact clinical outcomes.
Objective The purpose of this study was to estimate pharmacokinetic parameters and to evaluate placental transport of 17-hydroxyprogesterone caproate (17-OHPC) in singleton gestation. Study Design ...Sixty-one women who received weekly injections of 17-OHPC underwent 2 pharmacokinetic studies at 20 + 0 to 24 + 6 weeks' gestation (study 1) and 31 + 0 to 34 + 6 weeks' gestation (study 2); daily blood samples were obtained between injections. In 18 women, blood samples were obtained over a 28-day period beyond the last injection (extended study). Maternal and/or cord blood were obtained at delivery. Results The half-life (median ± SD) of 17-OHPC was 16.2 ± 6 days. Concentrations of 17-OHPC were higher during study 2 than during study 1. Body mass index affected maternal 17-OHPC concentrations. Cord:maternal 17-OHPC concentration ratios averaged 0.2; 17-OHPC was detectible in cord plasma 44 days after the last maternal injection. Conclusion The apparent half-life of 17-OHPC is long, and pharmacokinetic parameters vary widely between subjects and are affected by maternal body mass index. The drug crosses the placental barrier.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purpose
To characterize prednisone use in pregnant women with rheumatoid arthritis using individual‐level heat‐maps and clustering individual trajectories of prednisone dose, and to evaluate the ...association between prednisone dose trajectory groups and gestational length.
Methods
This study included pregnant women with rheumatoid arthritis who enrolled in the MotherToBaby Autoimmune Diseases in Pregnancy Study (2003–2014) before gestational week 20 and reported prednisone use without another oral glucocorticoid during pregnancy (n = 254). Information on medication use and pregnancy outcomes was collected by telephone interview plus by medical record review. Prednisone daily dose and cumulative dose were plotted by gestational day using a heat map for each individual. K‐means clustering was used to cluster individual trajectories of prednisone dose into groups. The associations between trajectory group and demographics, disease severity measured by the Health Assessment Questionnaire at enrollment, and gestational length were evaluated.
Results
Women used prednisone 3 to 292 days during pregnancy, with daily doses ranging from <1 to 60 mg. Total cumulative dose ranged from 8 to 6225 mg. Disease severity, non‐biologic disease modifying anti‐rheumatic drug use, and gestational length varied significantly by trajectory group. After adjusting for disease severity, non‐biologic disease modifying anti‐rheumatic drug use, and other covariates, the highest vs lowest daily dose trajectory group was associated with reduced gestational age at delivery (β: −2.3 weeks (95%: −3.4, −1.3)), as was the highest vs lowest cumulative dose trajectory group (β: −2.6 weeks (95%: −3.6, −1.5)).
Conclusions
In pregnant women with rheumatoid arthritis, patterns of higher prednisone dose were associated with shorter gestational length compared with lower dose.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Vitamin D(3) is critical for the regulation of calcium and phosphate homeostasis. In some individuals, mineral homeostasis can be disrupted by long-term therapy with certain antiepileptic drugs and ...the antimicrobial agent rifampin, resulting in drug-induced osteomalacia, which is attributed to vitamin D deficiency. We now report a novel CYP3A4-dependent pathway, the 4-hydroxylation of 25-hydroxyvitamin D(3) (25OHD(3)), the induction of which may contribute to drug-induced vitamin D deficiency. The metabolism of 25OHD(3) was fully characterized in vitro. CYP3A4 was the predominant source of 25OHD(3) hydroxylation by human liver microsomes, with the formation of 4β,25-dihydroxyvitamin D(3) 4β,25(OH)(2)D(3) dominating (V(max)/K(m) = 0.85 ml · min(-1) · nmol enzyme(-1)). 4β,25(OH)(2)D(3) was found in human plasma at concentrations comparable to that of 1α,25-dihydroxyvitamin D(3), and its formation rate in a panel of human liver microsomes was strongly correlated with CYP3A4 content and midazolam hydroxylation activity. Formation of 4β,25(OH)(2)D(3) in primary human hepatocytes was induced by rifampin and inhibited by CYP3A4-specific inhibitors. Short-term treatment of healthy volunteers (n = 6) with rifampin selectively induced CYP3A4-dependent 4β,25(OH)(2)D(3), but not CYP24A1-dependent 24R,25-dihydroxyvitamin D(3) formation, and altered systemic mineral homeostasis. Our results suggest that CYP3A4-dependent 25OHD(3) metabolism may play an important role in the regulation of vitamin D(3) in vivo and in the etiology of drug-induced osteomalacia.
Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of >20% of marketed drugs. CYP2D6 expression and activity exhibit high interindividual variability and is induced during pregnancy. The ...farnesoid X receptor (FXR) is a transcriptional regulator of CYP2D6 that is activated by bile acids. In pregnancy, elevated plasma bile acid concentrations are associated with maternal and fetal risks. However, modest changes in bile acid concentrations may occur during healthy pregnancy, thereby altering FXR signaling. A previous study demonstrated that hepatic tissue concentrations of bile acids positively correlated with the hepatic mRNA expression of CYP2D6. This study sought to characterize the plasma bile acid metabolome in healthy women (
= 47) during midpregnancy (25-28 weeks gestation) and ≥3 months postpartum and to determine if plasma bile acids correlate with CYP2D6 activity. It is hypothesized that during pregnancy, plasma bile acids would favor less hydrophobic bile acids (cholic acid vs. chenodeoxycholic acid) and that plasma concentrations of cholic acid and its conjugates would positively correlate with the urinary ratio of dextrorphan/dextromethorphan. At 25-28 weeks gestation, taurine-conjugated bile acids comprised 23% of the quantified serum bile acids compared with 7% ≥3 months postpartum. Taurocholic acid positively associated with the urinary ratio of dextrorphan/dextromethorphan, a biomarker of CYP2D6 activity. Collectively, these results confirm that the bile acid plasma metabolome differs between pregnancy and postpartum and provide evidence that taurocholic acid may impact CYP2D6 activity during pregnancy. SIGNIFICANCE STATEMENT: Bile acid homeostasis is altered in pregnancy, and plasma concentrations of taurocholic acid positively correlate with CYP2D6 activity. Differences between plasma and/or tissue concentrations of farnesoid X receptor ligands such as bile acids may contribute to the high interindividual variability in CYP2D6 expression and activity.
Changes in the maternal metabolome, and specifically the maternal lipidome, that occur during pregnancy are relatively unknown. The objective of this investigation was to evaluate the effects of ...pregnancy on sphingolipid levels using metabolomics analysis followed by confirmational, targeted quantitative analysis. We focused on three subclasses of sphingolipids: ceramides, sphingomyelins, and sphingosines. Forty-seven pregnant women aged 18 to 50 years old participated in this study. Blood samples were collected on two study days for metabolomics analysis. The pregnancy samples were collected between 25 and 28 weeks of gestation and the postpartum study day samples were collected ≥3 months postpartum. Each participant served as their own control. These samples were analyzed using a Ultra-performance liquid chromatography/mass spectroscopy/mass spectroscopy (UPLC/MS/MS) assay that yielded semi-quantitative peak area values that were used to compare sphingolipid levels between pregnancy and postpartum. Following this lipidomic analysis, quantitative LC/MS/MS targeted/confirmatory analysis was performed on the same study samples. In the metabolomic analysis, 43 sphingolipid metabolites were identified and their levels were assessed using relative peak area values. These profiled sphingolipids fell into three categories: ceramides, sphingomyelins, and sphingosines. Of the 43 analytes measured, 35 were significantly different during pregnancy (
< 0.05) (including seven ceramides, 26 sphingomyelins, and two sphingosines) and 32 were significantly higher during pregnancy compared to postpartum. Following metabolomics, a separate quantitative analysis was performed and yielded quantified concentration values for 23 different sphingolipids, four of which were also detected in the metabolomics study. Quantitative analysis supported the metabolomics results with 17 of the 23 analytes measured found to be significantly different during pregnancy including 11 ceramides, four sphingomyelins, and two sphingosines. Fourteen of these were significantly higher during pregnancy. Our data suggest an overall increase in plasma sphingolipid concentrations with possible implications in endothelial function, gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy, and fetal development. This study provides evidence for alterations in maternal sphingolipid metabolism during pregnancy.
Breast cancer resistance protein (BCRP) is most abundantly expressed in the apical membrane of placental syncytiotrophoblasts,
suggesting that it may protect the fetus by impeding drug penetration ...across the placental barrier. Glyburide (GLB) is an
antidiabetic drug routinely used to treat gestational diabetes. In this study, we first determined whether GLB is a BCRP/Bcrp1
substrate. The intracellular 3 HGLB concentrations in Madin-Darby canine kidney (MDCK)/BCRP cells were significantly lower than those in MDCK/vector cells.
The addition of 10 μM fumitremorgin C, a specific BCRP inhibitor, significantly increased the intracellular 3 HGLB concentrations approximately 2-fold in MDCK/BCRP cells, but it had no effect in MDCK/vector cells. Similar results were
obtained using MDCKII parent and MDCKII/Bcrp1 cells. GLB was also shown to be a BCRP/Bcrp1 substrate in transwell transport
experiments. We then examined whether Bcrp1 limits fetal distribution of GLB in the pregnant mouse. GLB was administered by
retro-orbital injection to the wild-type and Bcrp1 -/- pregnant mice. The maternal plasma samples and fetuses were collected at various times (0.5-240 min) after drug administration.
The GLB concentrations in the maternal plasma samples and homogenates of fetal tissues were determined by high-performance
liquid chromatography/mass spectrometry. Although the maternal plasma area under the concentration-time curves (AUCs) of GLB
in the wild-type and Bcrp1 -/- pregnant mice were comparable, the fetal AUC of GLB in the Bcrp1 -/- pregnant mice was approximately 2 times greater than that in the wild-type pregnant mice. These results suggest that GLB
is a BCRP/Bcrp1 substrate, and Bcrp1 significantly limits fetal distribution of GLB in the pregnant mouse, but it has only
a minor effect on the systemic clearance of the drug.
The mechanism of cytochrome P450 2D6 (CYP2D6) induction during pregnancy has not been evaluated in humans. This study assessed the changes in CYP2D6 and CYP3A activities during pregnancy and ...postpartum, and the effect of vitamin A administration on CYP2D6 activity. Forty‐seven pregnant CYP2D6 extensive metabolizers (with CYP2D6 activity scores of 1 to 2) received dextromethorphan (DM) 30 mg orally as a single dose during 3 study windows (at 25 to 28 weeks of gestation, study day 1; at 28 to 32 weeks of gestation, study day 2; and at ≥3 months postpartum, study day 3). Participants were randomly assigned to groups with no supplemental vitamin A (control) or with supplemental vitamin A (10 000 IU/day orally for 3 to 4 weeks) after study day 1. Concentrations of DM and its metabolites, dextrorphan (DX) and 3‐hydroxymorphinan (3HM), were determined from a 2‐hour post‐dose plasma sample and cumulative 4‐hour urine sample using liquid chromatography–mass spectrometry. Change in CYP2D6 activity was assessed using DX/DM plasma and urine metabolic ratios. The activity change in CYP3A was also assessed using the 3HM/DM urine metabolic ratio. The DX/DM urine ratio was significantly higher (43%) in pregnancy compared with postpartum (P = .03), indicating increased CYP2D6 activity. The DX/DM plasma ratio was substantially higher in the participants, with an activity score of 1.0 during pregnancy (P = .04) compared with postpartum. The 3HM/DM urinary ratio was significantly higher (92%) during pregnancy, reflecting increased CYP3A activity (P = .02). Vitamin A supplementation did not change CYP2D6 activity during pregnancy; however, plasma all‐trans retinoic acid (atRA) concentrations were positively correlated with increased CYP2D6 activity during pregnancy and postpartum. Further research is needed to elucidate the mechanisms of increased CYP2D6 activity during pregnancy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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