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ABSTRACT:The antidiabetic agent glyburide (glibenclamide) is frequently used for the treatment of type II diabetes and is increasingly being used for the treatment of gestational diabetes. Evidence suggests that breast cancer resistance protein/ATP-binding cassette, subfamily

Prescription and over-the-counter drug use during pregnancy is necessary for many women today. A study of US and Canadian women found that, on average, 2.3 drugs were used during pregnancy; however, 28% reported using more than 4. For some women, this is because they become pregnant with preexisting conditions that require ongoing or intermittent pharmacotherapy. For others, this is because pregnancy itself can give rise to new medical conditions such as gestational diabetes and preeclampsia. The principal concern of prescribing physicians is whether or not agents will harm the fetus (i.e., have teratogenic effects). This concern rose to prominence primarily as a result of the thalidomide disaster. Marketed for use in morning sickness, thalidomide was found to be a potent teratogen capable of producing a variety of birth defects relating to development. Consequently, determining the teratogenicity of new drugs currently dominates the objectives of pregnancy-relevant experiments conducted throughout drug development. This often comes at the expense of valuable pharmacokinetic (PK) studies, which are seldom performed pre-market. Sex differences in PK parameters have been demonstrated in animals and humans since the 1930s. It is, therefore, not surprising that differences also arise in pregnancy. A wide array of physiological and hormonal changes occur during pregnancy; most begin early in the first trimester and increase linearly until parturition. Physicians lacking adequate PK information typically prescribe the standard adult dose in pregnancy, and this can be either inadequate or excessive depending on a variety of factors. The purpose of this report is to highlight this issue and illustrate how current methods used to obtain PK data in pregnancy are insufficient. The steps that are being taken to address this issue will also be discussed.

Purpose The authors report a seven-year-old male, designated FR, with severe sensorineural hearing loss. Features include round face, hypertelorism, epicanthal folds, and flat nasal root. Although there were early developmental concerns, all but his speech delay resolved when he was placed in an educational program that accommodated his hearing loss. To investigate genetic causes for his hearing loss, genetic studies were performed. Methods History, physical examination, audiologic assessment, and imaging were performed according to usual practice. FMR1, GJB2, GJB6, and POU3F4 genes were sequenced. Chromosomal studies consisted of karyotyping and breakpoint analysis by fluorescence in situ hybridization (FISH). Results Results from FMR1, GJB2, GJB6, and POU3F4 sequencing and echocardiography, ECG, and abdominal ultrasound were normal. CT revealed a large fundus of the internal auditory canals and absence of the bony partition between the fundus and the adjacent cochlear turns with a widened modiolus bilaterally. CT findings are consistent with those described in persons with DFNX2 hereditary deafness. His karyotype was 46,inv(X)(q13q24),Y.ish inv(X)(XIST+)mat. FISH refined the breakpoints to inv(X)(q21.1q22.3). The Xq21.1 breakpoint was narrowed to a 25 kb region 450 kb centromeric to the DFNX2 gene, POU3F4. There are rare case reports of DFNX2 patients with chromosomal rearrangements positioned centromeric to POU3F4 and no mutations within the gene. Conclusions We hypothesize that FR's hearing loss is caused by dysregulation of POU3F4 due to separation from regulatory elements affected by the inversion.

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.

It is currently unknown whether gestational diabetes mellitus (GDM), a prevalent obstetrical complication, compounds the changes in drug disposition that occur naturally in pregnancy. Hyperlipidemia occurs in GDM. Using a rat model of GDM, we determined whether excess lipids compete with drugs for plasma protein binding. Because lipids activate nuclear receptors that regulate drug transporters and metabolic enzymes, we used proteome analysis to determine whether hyperlipidemia indirectly leads to the dysregulation of these proteins in the liver. GDM was induced on gestational day 6 (GD6) via streptozotocin injection. Controls received either vehicle alone or streptozotocin with subsequent insulin treatment. Liver and plasma were collected on GD20. Glyburide and saquinavir protein binding was determined by ultrafiltration, and an established solvent method was used for plasma delipidation. Proteomics analysis was performed by using isobaric tags for relative and absolute quantitation methodology with membrane-enriched hepatic protein samples. Relative to controls, GDM rat plasma contained more cholesterol and triglycerides. Plasma protein binding of glyburide and saquinavir was decreased in GDM. Delipidation normalized protein binding in GDM plasma. Proteins linked to lipid metabolism were strongly affected in the GDM proteomics data set, with prohyperlipidemic and antihyperlipidemic changes observed, and formed networks that implicated several nuclear receptors. Up-regulation of drug transporters and metabolic enzymes was observed (e.g., multidrug resistance 1/2, CYP2A1, CYP2B9, and CYP2D3). In this study, GDM-induced hyperlipidemia decreased protein binding and was associated with drug transporter and metabolic enzyme up-regulation in the liver. Both of these findings could change drug disposition in affected pregnancies, compounding changes associated with pregnancy itself.

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ABSTRACT:Lopinavir (LPV) is the preferred HIV protease inhibitor in pregnancy, but it is unknown if gestational diabetes mellitus (GDM) affects its disposition. Hepatic protein expression and plasma protein binding are altered in rodent models of GDM. Because LPV is influenced by hepatic transporters and metabolic enzymes and is highly protein bound, it was hypothesized that streptozotocininduced GDM would alter its disposition. Maternal and fetal tissues were collected from GDM rats and controls 45 min after LPV injection. In another cohort, fetuses were serially extracted 5 to 60 min after injection. LPV was quantified using liquid chromatography tandem mass spectrometry. Expression of relevant transporters, such as Multidrug resistance protein 1 (Mdr1), and cytochrome P450 3a2 (Cyp3a2), which metabolizes LPV in rodents, was measured in maternal liver via quantitative reverse transcriptase polymerase chain reaction and Western blot analysis. Expression of relevant transporters also was measured in placenta via quantitative reverse transcriptase polymerase chain reaction. Protein binding was determined by ultrafiltration. Relative to controls, we observed dramatically reduced maternal and fetal LPV exposure in GDM. Compared with controls, maternal hepatic Mdr1 and Cyp3a2 were up-regulated, and protein binding was reduced in the GDM group. Increased Mdr1-and Cyp3a2-mediated hepatobiliary clearance, coupled with a larger unbound LPV fraction, is likely to have facilitated hepatic elimination, thereby decreasing maternal and fetal exposure. Not surprisingly, up-regulation of Mdr1 and Cyp3a2's transcriptional regulator, pregnane X receptor, was demonstrated in maternal liver via Western blot analysis. Up-regulation of Mdr1 in placentas isolated from the GDM group likely also contributed to decreased fetal exposure to LPV. This study provides preclinical support for an as yet unreported drug-disease (LPV-GDM) interaction.