Ontogeny of P-Glycoprotein in Mouse Intestine, Liver, and Kidney

Mahmood, Burhan; Daood, Monica J.; Hart, Claudia; Hansen, Tonya Moen; Watchko, Jon F.

doi:10.2310/6650.2001.33969

Cited by 35 publications

(27 citation statements)

References 37 publications

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“…In earlier studies, developmental changes in MDR1/mdr1 protein levels have been examined in mice, rats, or humans using the monoclonal antibody C219. The findings of reduced C219 immunoreactivity from those studies have suggested decreased P-gp in the brain, liver, and kidney in fetal or immature animals compared with adults (Schuetz et al, 1995;Matsuoka et al, 1999;Mahmood et al, 2001;Watchko et al, 2001). In support of the protein data, two recent studies have determined, by semiquantitative PCR, that mdr1a expression in the mouse brain and mdr1a and mdr1b expression in the rat brain, liver, and kidney increased with maturation (Tsai et al, 2002;Rosati et al, 2003).…”

supporting

confidence: 54%

BRAIN CYCLOSPORIN A LEVELS ARE DETERMINED BY ONTOGENIC REGULATION OFMDR1AEXPRESSION

Goralski

Acott²,

Fraser³

et al. 2005

Drug Metab Dispos

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supporting

confidence: 54%

BRAIN CYCLOSPORIN A LEVELS ARE DETERMINED BY ONTOGENIC REGULATION OFMDR1AEXPRESSION

Goralski

Acott²,

Fraser³

et al. 2005

Drug Metab Dispos

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“…Levels of mdr1b on the other hand, were all significantly different from adult, which the authors concluded indicates a steady, more gradual rise in expression. Contrary to these studies, Mahmood et al found no evidence for postnatal changes in renal P-gp (13). They used Western blotting to quantitate levels of protein and concluded that at all age groups, protein levels were 96 Ϯ 15% of adult levels.…”

Section: Discussionmentioning

confidence: 89%

“…Dutt (13,21,22). We used FVB mice in our study, similar to Mahmood et al The use of different techniques could also account for some differences seen.…”

Section: Discussionmentioning

confidence: 95%

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

et al. 2005

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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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“…Preweanling rats are shown to have relatively high GI absorption rates (Hoffman, 1982;Naylor and Harrison, 1995). Pglycoprotein, which may play a role as an efflux transporter of pyrethroids (Bain and LeBlanc, 1996;Buss et al, 2002) has been found to be deficient in young mice (Mahmood et al, 2001). Extensive absorption and/or decreased efflux from the GI tract of young animals could contribute to the higher internal exposure and toxicity of DLM.…”

Section: Age-dependent Toxic Signs Following Dlm Administrationmentioning

confidence: 99%

Ontogeny of Hepatic and Plasma Metabolism of Deltamethrin in Vitro: Role in Age-Dependent Acute Neurotoxicity

Anand¹,

Kim²,

Padilla³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Deltamethrin (DLM) is a relatively potent and widely used pyrethroid insecticide. Inefficient detoxification has been proposed to be the primary reason for the greater sensitivity of immature rats to the acute neurotoxicity of DLM. The objective of this study was to test this hypothesis by characterizing the age dependence of DLM metabolism in vitro, as well as toxic signs and blood levels of the neurotoxic parent compound following administration of 10

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Ontogeny of P-Glycoprotein in Mouse Intestine, Liver, and Kidney

Abstract: We conclude that Pgp is expressed in a tissue-specific and developmentally regulated fashion and speculate that developmental modulation of intestine-Pgp expression may affect the oral bioavailability of Pgp substrates.

Cited by 35 publications

References 37 publications

BRAIN CYCLOSPORIN A LEVELS ARE DETERMINED BY ONTOGENIC REGULATION OFMDR1AEXPRESSION

BRAIN CYCLOSPORIN A LEVELS ARE DETERMINED BY ONTOGENIC REGULATION OFMDR1AEXPRESSION

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

Ontogeny of Hepatic and Plasma Metabolism of Deltamethrin in Vitro: Role in Age-Dependent Acute Neurotoxicity

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