LAUSR

Background The kidney has a critical role in disposition, efficacy and toxicity of drugs and xenobiotics. Developmental changes of renal membrane transporters have the potential to explain population variability in paediatric pharmacokinetics and -dynamics of drugs but data are missing. We aimed to further delineate the expression of human renal tubular transporters multidrug resistance-associated protein (MRP) 4 and MRP2 and study localization in paediatric kidney samples. Methods We planned to semi-quantify expression levels and to study the age-specific localization of the transporters MRP4 and MRP2 with immunohistochemistry on 44 human neonatal and paediatric kidney samples with age range of 24,00 - 40,00 weeks gestational age (GA) and 0,29 - 744 weeks post-natal age (PNA). The staining intensity was semi-quantitatively scored by two independent observers (MB and BG). Results MRP4 is found to be localized at the apical membrane of the renal proximal tubules at 27 weeks of GA (n=3, 1,29- 4 weeks PNA) and no age-related changes of expression levels were detected. In a premature neonate of 24 weeks GA (n=1), no MRP4 was detected. The MRP2 staining did not meet the requirements to be scored and was rejected. Conclusion MRP4 is expressed from at least 27 weeks GA onwards and does not show developmental changes. The localization was similar as in adults (Ritter et al., 2005). The half-life of the MRP4 substrate furosemide was found to be 6 to 20-fold longer in neonates than in adults (Pacifici, G.M., 2013). This could potentially be linked with the absence of MRP4 in a premature neonate with GA 24 weeks. However, these data should be confirmed as we only had 1 sample of ±24 weeks GA available. Moreover, our data help us in understanding altered disposition of transporter substrates in paediatrics. References Pacifici, G. M. ( 2013). Clinical pharmacology of furosemide in neonates: a review. Pharmaceuticals;6(9):1094–1129. Ritter CA, Jedlitschky G, Meyer zu Schwabedissen H, Grube M, Köck K, & Kroemer HK. ( 2005). Cellular export of drugs and signaling molecules by the ATP-binding cassette transporters MRP4 (ABCC4) and MRP5 (ABCC5). Drug metabolism reviews;37(1):253–278. Disclosure(s) Nothing to disclose