Ontogeny of Renal P-glycoprotein Expression in Mice: Correlation with Digoxin Renal Clearance

Abstract

Digoxin is eliminated mainly by the kidney through glomerular filtration and P-glycoprotein (P-gp) mediated tubular secretion. Toddlers and young children require higher doses of digoxin per kilogram of bodyweight than adults, although the reasons for this have not been elucidated. We hypothesized there is an age-dependant increase in P-gp expression in young children. The objectives of this study were to elucidate agedependant expression of renal P-gp and its correlation with changes in the clearance rate of digoxin. FVB mice were killed at different ages to prepare total RNA for P-gp expression studies. Semi-quantitative RT-PCR was conducted to analyze mdr1a and mdr1b ontogeny in the kidney at: birth, 7, 14, 21, 28 and 45-d old adults. The pharmacokinetics of digoxin (7 g/kg)was studied in mice of the same age groups. 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. Digoxin clearance rates were the highest at Day 21, with significant correlation between P-gp expression and clearance values. Increases in digoxin clearance rates after weaning may be attributed, at least in part, to similar increases in P-gp expression. The kidney is a major port of exit from the body for numerous drugs and/or their metabolites. The ontogeny of renal handling of drugs has been considered in depth only in the context of low clearance rates in newborn infants in both clinical and experimental studies. Yet, there is evidence that in the post neonatal period, the young child needs much larger doses of renally excreted drugs compared with older children and adults. In the case of digoxin, which is frequently used in pediatrics and excreted mostly by the kidney, a neonate typically requires a daily dose of 5 g/kg, the toddler and young child need 10 -12 g/kg per day, whereas older children and adults need 8 -10 g/kg and 3-5 g/kg respectively (1).The mechanisms underlying these developmental changes have not been elucidated. The kidney clears most of the body load of digoxin by both glomerular filtration and tubular secretion, with digoxin half-lives in children varying consistently with renal clearance (2,3). Tubular secretion of digoxin is mediated by the P-glycoprotein (P-gp) transporter, encoded by the mdr1 gene (4). Presently, the ontogeny of renal P-gp has been sparsely studied and never linked directly to the elimination characteristics of digoxin, or other P-gp substrates. Whereas P-gp in humans is encoded by the one gene, MDR1, there are two genes responsible for encoding this drug transporter in murine kidney: mdr1a and mdr1b (5,6). The two genes are believed to have risen through gene duplication from a common precursor (7). Mdr1b was shown to be expressed at high levels in the pregnant uterus and the adrenal gland and expressed at intermediate levels in kidney and heart tissue (5). Longer exposures also revealed limited expression in muscle, brain, liver, spleen, and lungs. On the other hand, mdr1a is expressed at high levels in ...

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