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Impact of Viral Inflammation on the Expression of Renal Drug Transporters in Pregnant Rats.

ABSTRACT: Inflammation impacts the expression and function of drug transporters at term-gestation; however, the impact of inflammation on the expression of drug transporters at mid-gestation is largely unknown. Since renal drug transporters play a key role in the clearance of many drugs prescribed during pregnancy, our objective was to study the impact of the viral mimetic poly I:C on the expression of renal transporters in pregnant rats at mid-gestation. Poly I:C (10 mg/kg) or saline was administered intraperitoneally to pregnant Sprague-Dawley rats on gestational day 14. Expression of renal transporters was measured at 6, 24, and 48 h by qRT-PCR and Western blot. The mRNA levels of Mdr1a, Mrp4, Oct2, Octn1, Octn2, Mate1, Oat1-3, Urat1, Oatp4c1, Ent1, and Pept2 were significantly lower in the poly I:C group at 6 h. At 24 h, only the mRNA levels of Oct2, Oatp4c1, and Ent1 were decreased compared to saline. Poly I:C significantly decreased protein expression of Urat1 at 24 h, and P-gp, Oct2, Mate1, Oat1, Oat3 at 48 h,. Poly I:C imposed significant reductions in the expression of several key renal transporters at mid-gestation in pregnant rats. Thus, viral infection may impact renal excretion of drug transporter substrates, potentially leading to drug-disease interactions.

SUBMITTER: Karimian Pour N

PROVIDER: S-EPMC6956294 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Impact of Viral Inflammation on the Expression of Renal Drug Transporters in Pregnant Rats.

Karimian Pour Navaz N McColl Eliza R ER Piquette-Miller Micheline M

Pharmaceutics 20191122 12

Inflammation impacts the expression and function of drug transporters at term-gestation; however, the impact of inflammation on the expression of drug transporters at mid-gestation is largely unknown. Since renal drug transporters play a key role in the clearance of many drugs prescribed during pregnancy, our objective was to study the impact of the viral mimetic poly I:C on the expression of renal transporters in pregnant rats at mid-gestation. Poly I:C (10 mg/kg) or saline was administered int ...[more]

PMID: 31766631

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Project description:Seizure-provoking factors circulate late in gestation during normal pregnancy, but do not readily gain access to the brain due to the protective nature of the blood-brain barrier. In particular, efflux transporters are powerful ATP-driven pumps that actively prevent unwanted compounds from entering the brain. We hypothesized that acute inhibition of efflux transporters at the blood-brain barrier would result in spontaneous seizures in pregnant rats. We further hypothesized that the blood-brain barrier protects the maternal brain from seizure by increasing expression and/or activity of p-glycoprotein (P-gp), a major efflux transporter. Main blood-brain barrier efflux transporters were inhibited in-vivo in nonpregnant (Nonpreg) and pregnant (Preg; d19) Sprague Dawley rats (n=8/group). Seizures were monitored in conscious animals for 8h via chronically implanted electroencephalography (EEG) electrodes in the hippocampus and motor cortex and time-synced video. P-gp activity was measured via a calcein accumulation assay in freshly isolated cortical and hippocampal capillaries from Preg (d20) and Nonpreg rats (n=8-16/group), to assess regional susceptibility to transporter inhibition. P-gp expression, capillary density, and microglial activation as a measure of neuroinflammation were quantified using immunohistochemistry (n=4-6/group). Efflux transporter inhibition elicited hippocampal seizures within 1h in 100% of Preg rats that was not associated with neuroinflammation or elevated tumor necrosis factor alpha (TNF?) or vascular endothelial growth factor (VEGF), but negatively correlated with levels of estradiol. Hippocampal seizures were considerably less prevalent in Nonpreg rats. However, behavioral seizures in the motor cortex developed of similar severity in both groups of rats, demonstrating regional heterogeneity in response to efflux transporter inhibition. Basal P-gp activity was similar between groups, however, exposure to serum from Preg rats significantly decreased P-gp activity in the hippocampus, but not cortex, compared to serum from Nonpreg rats (0.29±0.1units/s in Preg vs. 0.06±0.02units/s in Nonpreg rats; p<0.05) that was not associated with elevated TNF? or VEGF. Thus, pregnancy differentially increased the susceptibility of the hippocampus to seizures in response to blood-brain barrier efflux transporter inhibition that may be due to the inhibitory effect of circulating factors in pregnancy on P-gp activity in the hippocampus.

Dataset Information

Impact of Viral Inflammation on the Expression of Renal Drug Transporters in Pregnant Rats.

Publications

Impact of Viral Inflammation on the Expression of Renal Drug Transporters in Pregnant Rats.

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