Physiological regulation of P‐glycoprotein, MRP1, MRP2 and cytochrome P450 3A2 during rat ontogeny

Rosati, Anna; Maniori, Silvia; Decorti, Giuliana; Candussio, Luigi; Giraldi, Tullio; Bartoli, Fiora

doi:10.1046/j.1440-169x.2003.00699.x

Cited by 60 publications

(63 citation statements)

References 35 publications

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“…The group detected abruptly high levels of mdr1b at 21 d (21), but no formal statistical analysis was presented. Rosati et al also demonstrated regulation of P-gp postnatally (22). They found that levels of both mdr1a and mdr1b at birth had significant increases from postnatal Day 6 onwards in the kidney, which corresponds to our Day 7.…”

Section: Discussionmentioning

confidence: 84%

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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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Section: Discussionmentioning

confidence: 84%

“…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: 99%

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

et al. 2005

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“…The mRNA expression levels of Mdr1a, Mdr1b and Mrp2 transcripts are relatively low in fetal and neonatal rats but, after birth, increase dramatically, and reach adult levels at 3 to 5 weeks old. However, the expression level of Mrp1 transcript does not show any modulation (Rosati et al, 2003).…”

Section: Functionmentioning

confidence: 89%

Children's toxicology from bench to bed - Drug-induced Renal Injury (4): Effects of nephrotoxic compounds on fetal and developing kidney

Suzuki

2009

J. Toxicol. Sci.

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“…Only one report did not detect MRP in human heart (Sugawara et al, 1997). MRP1 mRNA was found to be abundant in the heart of CD1 mice and chickens by Northern blot analysis, and in rats by RT-PCR (Stride et al, 1996;Hagen et al, 2000;Rosati et al, 2003). Moreover, Ghosh et al (2004) observed cardiac MRP1 gene expression by PCR in heart of Wistar rats, which was increased in diabetic cardiomyocytes.…”

Section: Abc Transporters and Distribution Of Drugs To The Heartmentioning

confidence: 99%

“…Further work is required to elucidate the precise biological functions of ABCD2 and ABCA transporters. Rosati et al, (2003) studied the physiological modulation of mdr1a, mdr1b, mrp1 and mrp2 in some tissues including the heart during rat ontogeny. In this research in which hearts were collected at different developmental stages, both mdr1a and mdr1b levels of transcript were detected by RT-PCR and increased during rat ontogeny to obtain the highest levels at 30 and/or 60 days of age.…”

Section: Abc Transporters and Distribution Of Drugs To The Heartmentioning

confidence: 99%

The ATP-Binding Cassette Transporters and Their Implication in Drug Disposition: A Special Look at the Heart

Couture

Nash²,

Turgeon³

2006

Pharmacol Rev

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Physiological regulation of P‐glycoprotein, MRP1, MRP2 and cytochrome P450 3A2 during rat ontogeny

Cited by 60 publications

References 35 publications

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

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

Children's toxicology from bench to bed - Drug-induced Renal Injury (4): Effects of nephrotoxic compounds on fetal and developing kidney

The ATP-Binding Cassette Transporters and Their Implication in Drug Disposition: A Special Look at the Heart

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