Ontogeny of renal P-glycoprotein expression in mice: correlation with digoxin renal clearance.
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 age-dependant 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 microg/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.
Pinto
Natasha
N
Division of Clinical Pharmacology, The Hospital for Sick Children, and Department of Pharmacology, University of Toronto, Ontario, Canada.
Halachmi
Naomi
N
Verjee
Zulfikarali
Z
Woodland
Cindy
C
Klein
Julia
J
Koren
Gideon
G
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D001835:Body Weight; D004077:Digoxin / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D009929:Organ Size; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D004077:Digoxin; D012333:RNA, Messenger; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3