Ontogeny of renal P-glycoprotein expression in mice: implications for pediatric dosing

Abstract

Background Digoxin is eliminated mainly by the kidneys through glomerular filtration and P-glycoprotein (P-gp), a drug efflux pump. Children require higher doses of digoxin than adults, although the reasons for this have not been fully elucidated. Given that the renal clearance of digoxin is higher in children, we hypothesize there is an increase in P-gp expression in young children. We studied this in mice, where P-gp in encoded by both the mdr1a and mdr1b genes. Methods FVB mice were sacrificed at different ages to prepare total RNA for P-gp expression studies. Semi-quantitative RT-PCR was conducted to analyse mdr1a and mdr1b ontogeny in the kidney at: birth, 7, 14, 21, 28 and 45-day old adults. The results were analyzed by t-tests or rank sum tests. Clearance studies of digoxin (7 μg/kg), inulin (100 mg/kg) and PAH (100 mg/kg) were carried out in the same age groups. Results Newborn and Day 7 levels of both mdr1a and mdr1b were marginal. Day 21 mdr1b levels were significantly higher than both Day 14 and Day 28 levels but not adult. For mdr1a, only Day 28 was significantly lower than adult levels. Preliminary digoxin clearance results suggest a higher clearance rate at Day 21. Conclusion mdr1b levels increase after infancy, appear to peak at Day 21 (weaning), decrease at Day 28 and then stabilize at adult levels. This suggests an ontogeny of renal P-gp, with implications that younger children may need substantially more drug. Clinical Pharmacology & Therapeutics (2004) 75, P25–P25; doi: 10.1016/j.clpt.2003.11.092