PT  - JOURNAL ARTICLE
AU  - Derina E Sweeney
AU  - Volker Vallon
AU  - Timo Rieg
AU  - Wei Wu
AU  - Thomas F Gallegos
AU  - Sanjay K. Nigam
TI  - Functional Maturation of Drug Transporters in the developing, neonatal and postnatal Kidney
AID  - 10.1124/mol.110.070680
DP  - 2011 Jan 01
TA  - Molecular Pharmacology
PG  - mol.110.070680
4099  - http://molpharm.aspetjournals.org/content/early/2011/04/14/mol.110.070680.short
4100  - http://molpharm.aspetjournals.org/content/early/2011/04/14/mol.110.070680.full
AB  - Since renal function in newborns is immature, the pharmacokinetics of drugs administered to neonates vary significantly from adult patients. The establishment of drug transport systems is a key process in the functional maturation of the nephron. However, a thorough examination of the expression of the main drug transporters in the kidney throughout all stages of development (embryonic, postnatal and mature) has yet to be carried out and the functional (physiological) impact is not well understood. Using time-series microarray data, we analyzed the temporal behavior of mRNA levels for a wide range of transporters in the rodent kidney throughout a developmental time series. We find dynamic increases between the postnatal and mature stages of development for a number of transporters, including the proximal tubule-specific drug and organic anion transporters (OATs) OAT1 and OAT3. The OATs are the major multispecific basolateral drug, toxin and metabolite transporters in the proximal tubule responsible for handling of many drugs, as well as the prototypical OAT substrate p-aminohippurate (PAH). We therefore performed specific in vivo pharmacokinetic analysis of the transport of PAH in postnatal and maturing rodent kidney. We show that there is a 4 fold increase in PAH clearance during this period. Clearance studies in Oat1 and Oat3 knockouts confirm that, as in the adult, Oat1 is the principle transporter of PAH in the postnatal kidney. The substantial differences observed supports the need for better understanding of pharmacokinetics in the newborn and juvenile kidney compared to the adult kidney at the basic and clinical level.