This project, entitled Developmental Aspects of Aminopenicillin Renal Clearance, is submitted as Research Project 3 of an application responsive to RFA-HD-10-026: Specialized Center in Research in Pediatric Developmental Pharmacology Program (U54). The overall theme of the proposed program at the University of California, San Diego, is to bring together non-clinical and clinical experts in the fields of developmental physiology, pharmacology, and infectious diseases to advance the field of pediatric developmental pharmacology. Project 3 achieves this purpose by bringing together Dr. Sanjay Nigam, a basic scientist with an expertise in renal morphogenesis and the discoverer of organic anion transporter (Oat) 1 critical to aminopenicillin excretion, and the expertise in pediatric pharmacokinetic modeling and pediatric clinical trials described in the overall proposal. The purpose of Project 3 is to the elucidate the age- and developmentally-related changes in the SLC22 family of solute carrier proteins in the kidney, which are critical in the handling and elimination of several commonly-used, yet potentially toxic drugs in children, including diuretics, antivirals, and antiretrovirals. Thus in the first part of the project, transcriptomic analysis will be undertaken to determine the pattern of expression for SLC22 transporters in the maturing kidney. Since these transport proteins also play an essential role In the handling and elimination of a wide variety of key metabolites, metabolite excretion will also be examined during postnatal and juvenile development. The first part of the project is aimed at the creation of a predictive systems model of the transcriptomic and metabolomic response of the renal SLC22 drug transporters during kidney maturation in neonatal and juvenile rats. Simultaneously, pharmacokinetic analysis of aminopenicillin in postnatal and juvenile rats will be undertaken to obtain provide important information about the renal clearance of aminopenicillins in neonatal development and the relationship between SLC22 substrates and aminopenicillin excretion. The model derived from the rat studies will be used to refine the pediatric PK model to establish a comprehensive renal transporter model designed to generate rational dosing guidelines.
The kidney is the primary route of elimination of many antimicrobials. This is accomplished by in part by active transport and the developmental characteristics of this pathway are poorly understood. Changes in transporter function can affect systemic antimicrobial concentrations and need to be considered for effective dosing. These transporters may also alter renal tissue exposure and play a role in nephrotoxicity of drugs.
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