Functional Maturation of Drug Transporters in the Developing, Neonatal, and Postnatal Kidney

Abstract

Because 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 SLC and ABC 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 (SLC22a6) and OAT3 (SLC22a8). 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 para-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 with the adult kidney at the basic and clinical level.

Hepatocyte Nuclear Factors 4αand 1αRegulate Kidney Developmental Expression of Drug-Metabolizing Enzymes and Drug Transporters

“…By E20, late differentiation events are occurring, although new nephrons are still being formed; importantly, at this time point, the kidney is naïve to the influences of birth and the extrauterine environment. At P13, new nephrons are no longer being formed (Larsson, 1975), but the transcriptional profile or functional capacity has not yet reached mature levels (Sweeney et al, 2011). Finally, the proximal tubule reaches maturity after puberty, which occurs around 4-6 weeks in rodents.…”

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

“…For example, it is known that drug transporter expression occurs early in embryogenesis; indeed, several renal drug transporters are expressed transiently in the developing central nervous system and other tissues (94). Late in rodent gestation, the expression is largely limited to the future proximal tubules of the kidney (15,95); thereafter, there is a burst in renal expression around the time of birth, eventually reaching (and perhaps overshooting for a short time) adult expression (9,96). This is paralleled by functional changes, such as increasing PAH clearance (96).…”

“…Late in rodent gestation, the expression is largely limited to the future proximal tubules of the kidney (15,95); thereafter, there is a burst in renal expression around the time of birth, eventually reaching (and perhaps overshooting for a short time) adult expression (9,96). This is paralleled by functional changes, such as increasing PAH clearance (96). There is evidence in animals for a developmental inducibility window, during which renal drug transporters may, during the early postnatal period, be induced by substrates or by hormones (97,98).…”

Development of Metabolic Phenotype in Phenylketonuria: Evaluation of the Blaskovics Protein Loading Test at 5 Years of Age

“…In wild-type mice, the pAH clearance increases till 10 weeks of age. In adult mice, OAT1 is the principal pAH transporter (Sweeney et al 2011).…”