Safety concerns for fetus development of zidovudine (AZT) administration as prophylaxis of vertical transmission of HIV persist. We evaluated the participation of the ATP-binding cassette efflux transporter ABCG2 in the penetration of AZT into the fetal brain and the relevance for drug safety. Oral daily doses of AZT (60mg/kg body weight) or its vehicle were administered between post gestational days 11 (E11) and 20 (E20) to Sprague-Dawley pregnant rats. At E21, animals received an intravenous bolus of 60mg AZT/kg body weight in the presence or absence of the ABCG2 inhibitor gefitinib (20mg/kg body weight, ip) and AZT in maternal plasma and fetal brain were measured by HPLC-UV. ABCG2 protein expression in placenta and fetal brain, as well as mitochondrial function and ultrastructure in fetal brain were also analyzed. In utero chronic exposure to AZT markedly induced ABCG2 expression in placenta and fetal brain whereas did not significantly alter mitochondrial functionality in the fetal brain. The area-under-the-concentration-time-curve of AZT significantly decreased in fetal brains isolated from AZT-exposed fetuses compared to control group, but this effect was abolished by ABCG2 inhibition. Our results suggest that the absence of mitochondrial toxicity in the fetal brain after chronic in utero administration of AZT could be attributed to its low accumulation in the tissue caused, at least in part, by ABCG2 overexpression. We propose that any interference with ABCG2 activity due to genetic, pathological or iatrogenic factors would increase the amount of AZT reaching the fetal brain, which could increase the risk of toxicity of this drug on the tissue.

AP induced liver Pgp expression and activity in rats.Aimto study the effect of sub‐toxic doses of AP on intestinal Pgp expression in rats and in a human intestinal cell line.M&MMale Wistar rats were injected i.p. for 3 days with 0.2; 0.3; and 0.6 g/kg b.w. of AP (AP group) or vehicle (C group) (n=4). One day later Pgp expression and activity were evaluated by western‐blotting and rhodamine 123 (R123, 15 uM) serosal to mucosal transport in ileum isolated sacs with or without verapamil (V, 100 uM). Intestinal human LS174T cells were exposed to a sub‐toxic dose of AP (5 mM) for 48 hs, then Pgp expression was evaluated by QPCR and R123 efflux was determined by flow citometry with or without V.ResultsIleum Pgp expression increased in AP vs C (160%, P<0.05). Cumulative R123 secretion was 44% higher in AP group (P<0.05). V inhibited R123 transport in both AP and C. Cells exposed to AP expressed 60% more protein and presented 80% more activity than control cells (P<0.05).ConclusionSub‐toxic doses of AP induced intestinal Pgp expression and activity in rats and in a human intestinal cell line. This suggests potential drug‐drug interactions when AP is co‐administered with other Pgp substrates. Consistently, preliminary studies have shown induction of Pgp in a human intestinal cell line exposed to sub‐toxic concentrations of APAP.

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