Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Anger, G; Piquette-Miller, Micheline

doi:10.1124/dmd.111.040626

Cited by 14 publications

(17 citation statements)

References 43 publications

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“…This poly(I:C)-mediated downregulation is consistent with previous reports (Knickle et al, 1992;Petrovic and Piquette-Miller, 2010). As plasma levels of metabolites were not measured in this study, the resultant effect of poly(I:C) on the hepatic clearance of LPV is not immediately obvious; however, previous studies have demonstrated that LPV metabolite concentrations in rats are reflective of Cyp3a2 mRNA levels (Anger and Piquette-Miller, 2011). LPV is a highly extracted drug and is administered clinically with low-dose RTV to inhibit CYP3A enzymes and increase oral bioavailability.…”

Section: Discussionsupporting

confidence: 80%

“…Samples and standards were prepared as previously described (Anger and Piquette-Miller, 2011) using a liquid-liquid extraction adapted from Wang et al (2006). In brief, fetuses, placentas, and maternal livers were homogenized in deionized water.…”

Section: Methodsmentioning

confidence: 99%

“…Plasma and tissue LPV concentrations were measured using highperformance liquid chromatography-tandem mass spectrometry (LC-MS/ MS) as previously described (Anger and Piquette-Miller, 2011). In brief, for liquid chromatography, we used a CTC PAL autosampler (LEAP Technologies, Carrboro, NC) and an Agilent Technologies (Santa Clara, CA) 1100 series pump with a 50 Â 4.6-mm, 5-mm LiChrosorb RP-8 column (Phenomenex, Torrance, CA), while MS/MS was performed on an API 4000 triple quadrupole mass spectrometer equipped with a TurboIonSpray source (Applied Biosystems/MDS Sciex, Foster City, CA).…”

Section: Methodsmentioning

confidence: 99%

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Polyinosinic/Polycytidylic Acid–Mediated Changes in Maternal and Fetal Disposition of Lopinavir in Rats

Petrović

Piquette-Miller

2015

Drug Metab Dispos

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Maintenance of optimal lopinavir (LPV) concentration is essential for effective antiretroviral therapy and prevention of mother-tochild transmission of human immunodeficiency virus. However, little is known about the effects of inflammation on the pharmacokinetics of this protease inhibitor and drug transporter substrate, particularly during gestation. Our objective was to study the effect of polyinosinic/polycytidylic acid [poly(I:C)], a viral mimetic, on key maternal drug transporters, and to examine the effect on maternal and fetal disposition of LPV in rats. Poly(I:C) (5.0 mg/kg i.p.) or saline vehicle was administered to pregnant Sprague-Dawley rats on gestational days 17-18. At 24 hours postinjection, all rats were administered LPV (10 mg/kg i.v.), and plasma and tissues were collected at 5-120 minutes postadministration. Plasma interferon-g (IFN-g) levels were measured by enzyme-linked immunosorbent assay, and transporter expression was measured via real-time polymerase chain reaction. Maternal plasma, hepatic, placental, and fetal LPV concentrations were determined by liquid chromatography-tandem mass spectrometry. Administration of poly(I:C) induced IFN-g plasma levels and downregulated the expression of several important ATP-binding cassette (ABC) drug efflux transporters in the placenta and liver of pregnant rats, compared with controls (P < 0.05). Maternal LPV plasma concentration and area under the concentration-versus-time curve were significantly increased in the poly(I:C) group. Plasma protein binding was also significantly higher in poly(I:C)-treated rats. Pronounced increases in hepatic, placental, and fetal LPV tissue: unbound plasma concentrations were seen in the poly(I:C) group; however, absolute tissue concentrations were not changed. Since the majority of commonly used and clinically important antiretroviral drugs are known to be ABC transporter substrates, inflammation-mediated changes in transporter expression could affect their maternal disposition and fetal exposure.

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Section: Discussionsupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Polyinosinic/Polycytidylic Acid–Mediated Changes in Maternal and Fetal Disposition of Lopinavir in Rats

Petrović

Piquette-Miller

2015

Drug Metab Dispos

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“…It is possible that the increased levels of fatty acids observed in our HFD rats could have contributed to PXR activation and up-regulation of their target genes. High fat feeding was also associated with a substantial increase in the plasma concentrations of cholesterol, which probably contributes to PXR activation as recent studies have shown that PXR is activated by oxysterols, which are the oxidised derivatives of cholesterol (44,45) . With regard to the clinical implications of these findings, Cyp3a2, which corresponds to CYP3A in humans (46) , is responsible for the metabolism of the majority of drugs currently on the market (47) Pgp also plays a key role in the hepatobiliary clearance of many structurally diverse compounds including many anticancer, antiviral and anti-arrythmic drugs (48) .…”

Section: Discussionmentioning

confidence: 99%

Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition

et al. 2015

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More than 1·4 billion individuals are overweight or obese worldwide. While complications often require therapeutic intervention, data regarding the impact of obesity on drug disposition are scarce. As the influence of diet-induced obesity on drug transport and metabolic pathways is currently unclear, the objective of the present study was to investigate the effect of high fat feeding for 13 weeks in female Sprague -Dawley rats on the hepatic expression of the nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), liver X receptor (LXR) and farnesoid X receptor (FXR) and several of their target genes. We hypothesised that high fat feeding would alter the gene expression of major hepatic transporters through a dysregulation of the expression of the nuclear receptors. The results demonstrated that, along with a significant increase in body fat and weight, a high-fat diet (HFD) induced a significant 2-fold increase in the expression of PXR as well as a 2-, 5-and 2·5-fold increase in the hepatic expression of the PXR target genes Abcc2, Abcb1a and Cyp3a2, respectively (P,0·05). The expression levels of FXR were significantly increased in rats fed a HFD in addition to the increase in the expression levels of FXR target genes Abcb11 and Abcb4. The expression levels of both LXRa and LXRb were slightly but significantly increased in rats fed a HFD, and the expression levels of their target genes Abca1 and Abcg5, but not Abcg8, were significantly increased. The expression of the nuclear receptor CAR was not significantly altered between the groups. This suggests that a HFD may induce changes in the hepatobiliary transport and metabolism of endogenous and exogenous compounds.

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“…We have previously demonstrated that placental MDR1, MRP2 and BCRP mRNA expression is elevated in rat dams with streptozotocin-induced gestational diabetes mellitus (GDM) but nearly normal in rat dams with streptozotocin-induced GDM whose blood glucose was normalized following insulin treatment [16]. In the aforementioned study, relative to controls, fetal exposure to the MDR1 substrate lopinavir, a commonly used HIV protease inhibitor, was found to be dramatically lower in rat dams with streptozotocin-induced GDM [16].…”

Section: Introductionmentioning

confidence: 89%

Expression of ABC Efflux Transporters in Placenta from Women with Insulin-Managed Diabetes

2012

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Drug efflux transporters in the placenta can significantly influence the materno-fetal transfer of a diverse array of drugs and other xenobiotics. To determine if clinically important drug efflux transporter expression is altered in pregnancies complicated by gestational diabetes mellitus (GDM-I) or type 1 diabetes mellitus (T1DM-I), we compared the expression of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2) and the breast cancer resistance protein (BCRP) via western blotting and quantitative real-time polymerase chain reaction in samples obtained from insulin-managed diabetic pregnancies to healthy term-matched controls. At the level of mRNA, we found significantly increased expression of MDR1 in the GDM-I group compared to both the T1DM-I (p<0.01) and control groups (p<0.05). Significant changes in the placental protein expression of MDR1, MRP2, and BCRP were not detected (p>0.05). Interestingly, there was a significant, positive correlation observed between plasma hemoglobin A1c levels (a retrospective marker of glycemic control) and both BCRP protein expression (r = 0.45, p<0.05) and BCRP mRNA expression (r = 0.58, p<0.01) in the insulin-managed DM groups. Collectively, the data suggest that the expression of placental efflux transporters is not altered in pregnancies complicated by diabetes when hyperglycemia is managed; however, given the relationship between BCRP expression and plasma hemoglobin A1c levels it is plausible that their expression could change in poorly managed diabetes.

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Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Cited by 14 publications

References 43 publications

Polyinosinic/Polycytidylic Acid–Mediated Changes in Maternal and Fetal Disposition of Lopinavir in Rats

Polyinosinic/Polycytidylic Acid–Mediated Changes in Maternal and Fetal Disposition of Lopinavir in Rats

Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition

Expression of ABC Efflux Transporters in Placenta from Women with Insulin-Managed Diabetes

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