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.
Highlights
Viral infections during pregnancy have been linked to adverse pregnancy outcomes and birth defects including miscarriage, intrauterine growth restriction, preterm birth, microcephaly, and fetal death [1]
As compared to saline controls, the mRNA expression of IL-6, IL-1β, and tumor necrosis factor (TNF)-α in the kidneys was significantly higher in the polycytidilic acid (poly I):C-treated groups at 6 and 24 h
While the levels of IL-1β and TNF-α returned to baseline at 48 h, levels of IL-6 remained significantly higher at 48 h in the poly I:C-treated group (Figure 1)
Summary
Viral infections during pregnancy have been linked to adverse pregnancy outcomes and birth defects including miscarriage, intrauterine growth restriction, preterm birth, microcephaly, and fetal death [1]. A number of medications taken by pregnant women are excreted into the urine by renal drug transporters. Environmental factors such as inflammation can impact the expression and function of drug transporters [2,3,4,5,6,7,8]. Inflammation-elicited alterations in renal transporter expression during pregnancy can potentially impact the maternal disposition of these medications, which could lead to adverse maternal and fetal outcomes. Due to the important role that drug transporters play in the elimination of numerous clinically relevant drugs prescribed during pregnancy, understanding the impact of inflammation on the expression of these transporters is clinically important
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