Hypoglycemics: Pharmacokinetic Considerations During Pregnancy

Klieger, Chagit; Pollex, Erika; Kazmin, Aleksey; Koren, Gideon

doi:10.1097/ftd.0b013e3181b385ba

Cited by 9 publications

(6 citation statements)

References 102 publications

(101 reference statements)

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“…However, IR is increased during pregnancy, and this may require a higher insulin dose 57,58. At present, there is no information about the effects of pregnancy on the PK/PD of any of the insulin analogs.…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of insulin analogs in special populations with type 2 diabetes mellitus

Morello¹

2011

IJGM

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IntroductionThe goal of insulin therapy in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) is to match as closely as possible normal physiologic insulin secretion to control fasting and postprandial plasma glucose. Modifications of the insulin molecule have resulted in two long-acting insulin analogs (glargine and detemir) and three rapid-acting insulins (aspart, lispro, and glulisine) with improved pharmacokinetic/pharmacodynamic (PK/PD) profiles. These agents can be used together in basal-bolus therapy to more closely mimic physiologic insulin secretion patterns.MethodsThis study reviews effects of the multiple demographic and clinical parameters in the insulin analogs glargine, detemir, lispro, aspart, and glulisine in patients with T2DM. A search was conducted on PubMed for each major topic considered (effects of injection site, age, race/ethnicity, obesity, renal or hepatic dysfunction, pregnancy, exercise, drug interactions) using the topic words and name of each type of insulin analog. Information was also obtained from the prescribing information for each insulin analog.ResultsThe PK/PD profiles for insulin analogs may be influenced by many variables including age, weight, and hepatic and renal function. However, these variables do not have equivalent effects on all long-acting or rapid-acting insulin analogs.ConclusionRapid-acting and long-acting insulin analogs represent major advances in treatment for patients with T2DM who require insulin therapy. However, there are potentially important PK and PD differences between the two long-acting agents and among the three rapid-acting insulin analogs, which should be considered when designing treatment regimens for special patient groups.

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Section: Resultsmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of insulin analogs in special populations with type 2 diabetes mellitus

Morello¹

2011

IJGM

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“…Changes in maternal physiology include, among others, increased renal blood flow and glomerular filtration rate (GFR) (Davison and Hytten, 1975), as well as increased portal vein blood flow (Carlin and Alfirevic, 2008). 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).…”

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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“…It is well established that physiologic, biochemical, and hormonal changes during pregnancy can alter the pharmacokinetics (PK) of drugs throughout gestation (e.g., increased hepatic blood flow and glomerular filtration, and/or changes in the expression of drug-metabolizing enzymes and transporters) (Klieger et al, 2009). However, data are quite limited regarding the PK of glyburide during pregnancy, particularly in relation to gestational age.…”

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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Hypoglycemics: Pharmacokinetic Considerations During Pregnancy

Cited by 9 publications

References 102 publications

Pharmacokinetics and pharmacodynamics of insulin analogs in special populations with type 2 diabetes mellitus

Pharmacokinetics and pharmacodynamics of insulin analogs in special populations with type 2 diabetes mellitus

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

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