Clinical Therapeutics in Pregnancy

Feghali, Maisa; Mattison, Donald R.

doi:10.1155/2011/783528

Cited by 49 publications

(52 citation statements)

References 124 publications

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“…These physiologic changes alter important drug pharmacokinetics (PK) determinants such as GFR, oral absorption, plasma volume, and plasma protein binding (Anderson, 2005;Anger and Piquette-Miller, 2008;Klieger et al, 2009). Considerable data in the literature also suggest that expression and activities of drugmetabolizing enzymes and transporters are altered during pregnancy (Tracy et al, 2005;Hebert et al, 2008;Feghali and Mattison, 2011). In humans, cytochrome P450 (CYP) enzymes such as CYP2A6, CYP3A4, CYP2D6, and CYP2C9 demonstrate increased activities during pregnancy, whereas the activities of CYP1A2 and CYP2C19 are decreased (Dempsey et al, 2002;Anderson, 2005;Hodge and Tracy, 2007).…”

Section: Introductionmentioning

confidence: 99%

Gestational Age-Dependent Changes in Gene Expression of Metabolic Enzymes and Transporters in Pregnant Mice

et al. 2012

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Pregnancy-induced changes in drug pharmacokinetics can be explained by changes in expression of drug-metabolizing enzymes and transporters and/or normal physiology. In this study, we determined gestational age-dependent expression profiles for all metabolic enzyme and transporter genes in the maternal liver, kidney, small intestine, and placenta of pregnant mice by microarray analysis. We specifically examined the expression of genes important for xenobiotic, bile acid, and steroid hormone metabolism and disposition, namely, cytochrome P450s (Cyp), UDPglucuronosyltranserases (Ugt), sulfotransferases (Sult), and ATPbinding cassette (Abc), solute carrier (Slc), and solute carrier organic anion (Slco) transporters. Few Ugt and Sult genes were affected by pregnancy. Cyp17a1 expression in the maternal liver increased 3-to 10-fold during pregnancy, which was the largest observed change in the maternal tissues. Cyp1a2, most Cyp2 isoforms, Cyp3a11, and Cyp3a13 expression in the liver decreased on gestation days (gd) 15 and 19 compared with nonpregnant controls (gd 0). In contrast, Cyp2d40, Cyp3a16, Cyp3a41a, Cyp3a41b, and Cyp3a44 in the liver were induced throughout pregnancy. In the placenta, Cyp expression on gd 10 and 15 was upregulated compared with gd 19. Notable changes were also observed in Abc and Slc transporters. Abcc3 expression in the liver and Abcb1a, Abcc4, and Slco4c1 expression in the kidney were downregulated on gd 15 and 19. In the placenta, Slc22a3 (Oct3) expression on gd 10 was 90% lower than that on gd 15 and 19. This study demonstrates important gestational age-dependent expression of metabolic enzyme and transporter genes, which may have mechanistic relevance to drug disposition in human pregnancy.

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Section: Introductionmentioning

confidence: 99%

Gestational Age-Dependent Changes in Gene Expression of Metabolic Enzymes and Transporters in Pregnant Mice

et al. 2012

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“…In humans, M1 undergoes glucuronidation mediated by uridine 59-diphospho-glucuronosyltransferases (UGTs) and M2b is excreted unchanged in the urine (Naraharisetti et al, 2007). UGT1A1 and UGT1A4 expression is indeed induced during human pregnancy (Feghali and Mattison, 2011); however, mRNA levels of UGTs in pregnant mice are relatively unchanged (Shuster et al, 2013). Mechanisms of renal clearance (i.e., active tubular secretion and/or reabsorption) remain unknown for all glyburide metabolites Fetal/ maternal plasma glyburide concentration ratios.…”

Section: Discussionmentioning

confidence: 99%

“…Since hepatic CYP3A and CYP2C9 activities are significantly induced during human pregnancy Feghali and Mattison, 2011), cytochrome P450 induction could be one possible mechanism for the increased maternal glyburide clearance during pregnancy. Like in humans, glyburide clearance in pregnant mice was similarly doubled on gestation day (gd) 15 compared with nonpregnant controls (Zhou et al, 2010b), suggesting that the pregnant mouse may be an appropriate animal model to study glyburide PK during pregnancy.…”

Section: Abbreviations: [mentioning

confidence: 99%

Maternal-Fetal Disposition of Glyburide in Pregnant Mice Is Dependent on Gestational Age

Shuster

Risler

Liang

et al. 2014

J Pharmacol Exp Ther

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Gestational diabetes mellitus is a major complication of human pregnancy. The oral clearance (CL) of glyburide, an oral antidiabetic drug, increases 2-fold in pregnant women during late gestation versus nonpregnant controls. In this study, we examined gestational age-dependent changes in maternal-fetal pharmacokinetics (PK) of glyburide and metabolites in a pregnant mouse model. Nonpregnant and pregnant FVB mice were given glyburide by retro-orbital injection. Maternal plasma was collected over 240 minutes on gestation days (gd) 0, 7.5, 10, 15, and 19; fetuses were collected on gd 15 and 19. Glyburide and metabolites were quantified using high-performance liquid chromatography-mass spectrometry, and PK analyses were performed using a pooled data bootstrap approach. Maternal CL of glyburide increased approximately 2-fold on gd 10, 15, and 19 compared with nonpregnant controls. Intrinsic CL of glyburide in maternal liver microsomes also increased as gestation progressed. Maternal metabolite/glyburide area under the curve ratios were generally unchanged or slightly decreased throughout gestation. Total fetal exposure to glyburide was ,5% of maternal plasma exposure, and was doubled on gd 19 versus gd 15. Fetal metabolite concentrations were below the limit of assay detection. This is the first evidence of gestational age-dependent changes in glyburide PK. Increased maternal glyburide clearance during gestation is attributable to increased hepatic metabolism. Metabolite elimination may also increase during pregnancy. In the mouse model, fetal exposure to glyburide is gestational age-dependent and low compared with maternal plasma exposure. These results indicate that maternal glyburide therapeutic strategies may require adjustments in a gestational age-dependent manner if these same changes occur in humans.

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“…Pregnancy is associated with many physiologic changes that can influence drug absorption, distribution, metabolism, and excretion, such as an increase in gastric pH and reduction in intestinal motility, increased cardiac output, increased glomerular filtration rate, and reduced plasma albumin concentrations (Anderson, 2005;Feghali and Mattison, 2011). Although it is not surprising that the pregnant state cannot be represented simply by scalable changes in basic pharmacokinetic parameters (e.g., distribution volume and clearance) that take into account altered physiology, only recently has the research community begun to illuminate some of the profound changes in the biochemistry of drug metabolism and transport that occur during pregnancy.…”

Section: Introductionmentioning

confidence: 99%

Drug Metabolism and Transport During Pregnancy: How Does Drug Disposition Change during Pregnancy and What Are the Mechanisms that Cause Such Changes?

2013

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There is increasing evidence that pregnancy alters the function of drug-metabolizing enzymes and drug transporters in a gestationalstage and tissue-specific manner. In vivo probe studies have shown that the activity of several hepatic cytochrome P450 enzymes, such as CYP2D6 and CYP3A4, is increased during pregnancy, whereas the activity of others, such as CYP1A2, is decreased. The activity of some renal transporters, including organic cation transporter and P-glycoprotein, also appears to be increased during pregnancy. Although much has been learned, significant gaps still exist in our understanding of the spectrum of drug metabolism and transport genes affected, gestational age-dependent changes in the activity of encoded drug metabolizing and transporting processes, and the mechanisms of pregnancy-induced alterations. In this issue of Drug Metabolism and Disposition, a series of articles is presented that address the predictability, mechanisms, and magnitude of changes in drug metabolism and transport processes during pregnancy. The articles highlight state-of-the-art approaches to studying mechanisms of changes in drug disposition during pregnancy, and illustrate the use and integration of data from in vitro models, animal studies, and human clinical studies. The findings presented show the complex inter-relationships between multiple regulators of drug metabolism and transport genes, such as estrogens, progesterone, and growth hormone, and their effects on enzyme and transporter expression in different tissues. The studies provide the impetus for a mechanismand evidence-based approach to optimally managing drug therapies during pregnancy and improving treatment outcomes.

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Clinical Therapeutics in Pregnancy

Cited by 49 publications

References 124 publications

Gestational Age-Dependent Changes in Gene Expression of Metabolic Enzymes and Transporters in Pregnant Mice

Gestational Age-Dependent Changes in Gene Expression of Metabolic Enzymes and Transporters in Pregnant Mice

Maternal-Fetal Disposition of Glyburide in Pregnant Mice Is Dependent on Gestational Age

Drug Metabolism and Transport During Pregnancy: How Does Drug Disposition Change during Pregnancy and What Are the Mechanisms that Cause Such Changes?

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