O-36 A human proximal tubular epithelial cell model to explore a knowledge gap on neonatal drug disposition

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BackgroundFinding the right drug-dosage for neonates is still a medical challenge. Up to now, neonatal doses are extrapolated from adult and children doses. However, there are differences between neonatal and adult kidney physiology that should be put into consideration, especially when it comes to active drug metabolism. Studying renal drug clearances in neonates is limited by the lack of reliable human cell models. Our aim was to illustrate the feasibility to develop an in vitro model for neonatal proximal tubule epithelial cells (nPTECs) for studying renal drug clearances at this age.MethodnPTECs were isolated from urine samples of ne-onates of different gestational age (GA) and conditionally immortalised using a temperature sensitive SV40T anti-gen and human telomerase hTERT. The cell clones were characterised on gene expression level for PTECs markers such as P-glycoprotein (P-gp), aquaporin1 (AQP1), and organic cation transport protein 2 (OCT2). In addition, protein expression and functional assessment were per-formed for P-gp and OCT2.ResultsWe established 101 clonal cell lines of cinPTECs derived from neonatal urine. Gene expression analy-sis confirmed the expression of the PTECs (P-gp, AQP1, and OCT2), similar to the expression in the adult control ciPTECs. P-gp was expressed in cinPTECs from the differ-ent gestational ages and exhibited similar functionality as the adult derived ciPTECs. In contrast, OCT2 functionality was significantly lower in the cinPTECs cell lines com-pared to the adult ciPTECs.ConclusionWe demonstrate the feasibility of culturing cinPTECs expressing mature ciPTECs markers with high efficiency out of the urine samples of neonates. The cell model presented here can serve as a valuable tool to study proximal tubule physiology and pharmacology in new-borns. In addition, we demonstrate the physiolog-ical differences between the neonatal and adult kidney, which puts emphasise on the importance of studying drug pharmacokinetics in neonatal models instead of ex-trapolating from adult models.

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