Despite the large number of pregnant women and neonates infected with HIV receiving long-term treatment with antiretroviral agents, little is understood about the handling of these drugs in utero and in the neonatal kidney. Although the drugs are generally considered to be relatively safe for the fetus and neonate over the short-term, there is justifiable concern over undetected toxicities and long-term effects. This is part of a more general concern in pediatric pharmacology that unnecessary preterm and neonatal drug toxicity results from inappropriate dosing due to poorly understood mechanisms of maturation of drug handling capacity. With respect to drugs used for the treatment of HIV, in vitro data from the PI's group and others indicates that organic anion transporters (Oats), Oat1 and/or Oat3, are the key genes regulating antiretroviral handling. The PI's group was the first to identify Oat1, as well as a number of related genes, and has recently published the first adult Oat1 and Oat3 knockout mice data, which demonstrate defective organic anion (OA) transport and altered drug handling. However, the in vivo data in adult mice for certain OA compounds and drugs has revealed differences with in vitro data obtained mainly from Xenopus oocyte transport assays. Moreover, our recent developmental studies, using a novel ex-vivo method to analyze OA handling, suggest that Oat- independent mechanisms of OA transport may be important in utero and in neonates. Drawing on considerable preliminary data, in this REVISED application, we hypothesize that the mechanisms of in vivo OA drug transport are different in preterm and neonatal compared to adults. Furthermore, we hypothesize that, while Oat1 and Oat3 are the key antiretroviral transporters in adults and probably in the neonatal setting, in utero additional novel transporters also contribute to the handling of antiretrovirals used to treat HIV. These pathways need to be defined. We therefore aim to address the following questions: 1) What are the in vivo roles of Oat1 and Oat3 in net transport of antiretrovirals in the kidneys of neonatal wildtype and knockout animals? 2) Are additional pathways for transport of antiretrovirals active in utero? A combination of genetic, in vivo physiological, microarray and expression cloning methods will be employed to approach these questions, leveraging the joint strengths of the PI's group in OAT biology and kidney development. The results should provide key insights into the (likely different) mechanisms of drug handling in the in utero as well as neonatal settings and set the stage for translational studies. We have addressed all the criticisms of the prior application, including translational issues (please see letters from collaborators) and also provide new preliminary data.
Despite the large number of pregnant women and neonates infected with HIV receiving long-term treatment with antiretroviral agents, little is understood about the handling of these drugs in utero and in the neonatal kidney. This application attempts to address the basic scientific aspects of antiretroviral drug handling in the immature kidney.
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