Many drugs prescribed to children are drug transporter substrates. Drug transporters are membrane-bound proteins that mediate the cellular uptake or efflux of drugs and are important to drug absorption and elimination. Very limited data are available on the effect of age on transporter expression. Our study assessed agerelated gene expression of hepatic and intestinal drug transporters. Multidrug resistance protein 2 (MRP2), organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3 expression was determined in postmortem liver samples (fetal n = 6, neonatal n = 19, infant n = 7, child n = 2, adult n = 11) and multidrug resistance 1 (MDR1) expression in 61 pediatric liver samples. Intestinal expression of MDR1, MRP2, and OATP2B1 was determined in surgical small bowel samples (neonates n = 15, infants n = 3, adults n = 14). Using real-time reverse-transcription polymerase chain reaction, we measured fetal and pediatric gene expression relative to 18S rRNA (liver) and villin (intestines), and we compared it with adults using the 2 2ΔΔCt method. Hepatic expression of MRP2, OATP1B1, and OATP1B3 in all pediatric age groups was significantly lower than in adults. Hepatic MDR1 mRNA expression in fetuses, neonates, and infants was significantly lower than in adults. Neonatal intestinal expressions of MDR1 and MRP2 were comparable to those in adults. Intestinal OATP2B1 expression in neonates was significantly higher than in adults. We provide new data that show organ-and transporter-dependent differences in hepatic and intestinal drug transporter expression in an age-dependent fashion. This suggests that substrate drug absorption mediated by these transporters may be subject to age-related variation in a transporter dependent pattern.

Human renal membrane transporters play key roles in the disposition of renally cleared drugs and endogenous substrates, but their ontogeny is largely unknown. Using 184 human postmortem frozen renal cortical tissues (preterm newborns to adults) and a subset of 62 tissue samples, we measured the mRNA levels of 11 renal transporters and the transcription factor pregnane X receptor (PXR) with quantitative real-time polymerase chain reaction, and protein abundance of nine transporters using liquid chromatography tandem mass spectrometry selective reaction monitoring, respectively. Expression levels of p-glycoprotein, urate transporter 1, organic anion transporter 1, organic anion transporter 3, and organic cation transporter 2 increased with age. Protein levels of multidrug and toxin extrusion transporter 2-K and breast cancer resistance protein showed no difference from newborns to adults, despite age-related changes in mRNA expression. Multidrug and toxin extrusion transporter 1, glucose transporter 2, multidrug resistance-associated protein 2, multidrug resistance-associated protein 4 (MRP4), and PXR expression levels were stable. Using immunohistochemistry, we found that MRP4 localization in pediatric samples was similar to that in adult samples. Collectively, our study revealed that renal drug transporters exhibited different rates and patterns of maturation, suggesting that renal handling of substrates may change with age.

Background Pediatric drug development is hampered by practical, ethical, and scientific challenges. Microdosing is a promising new method to obtain pharmacokinetic data in children with minimal burden and minimal risk. The use of a labeled oral microdose offers the added benefit to study intestinal and hepatic drug disposition in children already receiving an intravenous therapeutic drug dose for clinical reasons. Objective The objective of this study was to present pilot data of an oral [14 C]paracetamol [acetaminophen (AAP)] microdosing study as proof of concept to study developmental pharmacokinetics in children.Methods In an open-label microdose pharmacokinetic pilot study, infants (0-6 years of age) received a single oral Conclusions We demonstrate the feasibility of using a [ 14 C]labeled microdose to study AAP pharmacokinetics, including metabolite disposition, in young children.Electronic supplementary material The online version of this article

KH176 is a potent intracellular reduction-oxidation-modulating compound developed to treat mitochondrial disease. We studied tolerability, safety, pharmacokinetics, pharmacodynamics, and efficacy of twice daily oral 100 mg KH176 for 28 days in a double-blind, randomized, placebo-controlled, two-way crossover phase IIA study in 18 adult m.3243A>G patients without cardiovascular involvement. Efficacy parameters included clinical and functional outcome measures and biomarkers. The trial was registered within ClinicalTrials.gov (NCT02909400), the European Clinical Trials Database (2016-001696-79), and ISRCTN (43372293) (The KHENERGY study). Twice daily oral 100 mg KH176 was well tolerated and appeared safe. No serious treatment-emergent adverse events were reported. No significant improvements in gait parameters or other outcome measures were obtained, except for a positive effect on alertness and mood, although a coincidence due to multiplicity cannot be ignored. The results of the study provide first data on safety and efficacy of KH176 in patients with mitochondrial disease and will be instrumental in designing future clinical trials.