The ontogeny of drug metabolizing enzymes and transporters in the rat

Zwart, Loeckie de; Scholten, Martijn; Monbaliu, Johan; Annaert, Pieter; Houdt, Jos M. Van; Wyngaert, Ilse Van den; Schaepdrijver, Luc M. De; Bailey, Graham P.; Coogan, Timothy P.; Coussement, W.; Mannens, Geert

doi:10.1016/j.reprotox.2008.09.010

Cited by 81 publications

(106 citation statements)

References 23 publications

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“…In vitro expression of rat organic cation transporters 1 and 2 indicated that they are basolaterally located transporters contributing to tubular secretion of cationic drugs, removing them from the plasma to be secreted in the urine (Urakami et al, 1998). In rats, renal transporter mRNA expression is increased in early adolescents (de Zwart et al, 2008). With developmental changes in transporter protein expression, it is predicted that the distribution and elimination of substrates would also change with age (de Zwart et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Nicotine Pharmacokinetics in Rats Is Altered as a Function of Age, Impacting the Interpretation of Animal Model Data

et al. 2014

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Several behavioral studies report that adolescent rats display a preference for nicotine compared with adults. However, age-related pharmacokinetic differences may confound the interpretation of these findings. Thus, differences in pharmacokinetic analyses of nicotine were investigated. Nicotine was administered via acute s.c. (1.0 mg base/kg) or i.v. (0.2 mg base/kg) injection to early adolescent (EA; postnatal day 25) and adult (AD; postnatal day 71) male Wistar rats. Nicotine and its primary metabolite, cotinine, and additional metabolites nornicotine, nicotine-19-N-oxide, trans-39-hydroxycotinine, and norcotinine were sampled from 10 minutes to 8 hours (plasma) and 2 to 8 hours (brain) post nicotine and analyzed by liquid chromatography-tandem mass spectrometry. Following s.c. nicotine, the EA cohort had lower levels of plasma nicotine, cotinine, and nicotine-19-N-oxide at multiple time points, resulting in a lower area under the plasma concentration-time curve (AUC) for nicotine (P < 0.001), cotinine (P < 0.01), and nicotine-19-Noxide (P < 0.001). Brain levels were also lower for these compounds. In contrast, the EA cohort had higher plasma and brain AUCs (P < 0.001) for the minor metabolite nornicotine. Brain-to-plasma ratios varied for nicotine and its metabolites, and by age. Following i.v. nicotine administration, similar age-related differences were observed, and this route allowed detection of a 1.6-fold-larger volume of distribution and 2-fold higher plasma clearance in the EA cohort compared with the AD cohort. Thus, unlike in humans, there are substantial age differences in nicotine pharmacokinetics such that for a given nicotine dose, adolescent rats will have lower plasma and brain nicotine compared with adults, suggesting that this should be considered when interpreting animal model data.

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Section: Discussionmentioning

confidence: 99%

Nicotine Pharmacokinetics in Rats Is Altered as a Function of Age, Impacting the Interpretation of Animal Model Data

et al. 2014

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“…Each drug has a different affinity for the plasma proteins, which can affect their available concentration. Zwart and colleagues looked at these levels in rats younger than six weeks and found that they are nearly half that of an adult level [158]. While this is an interesting developmental parameter to consider it is unlikely that this is the cause of the toxicity we observed.…”

Section: Preclinical Considerationsmentioning

confidence: 77%

“…In addition, it is necessary to consider the transporters for topotecan, since both drugs are given at the same time. Previous publications have found that mRNA expression of two of three transporters (multidrug resistance protein 1 and breast cancer resistance protein) in the kidney are greater as an adult than at birth; however, previous reports have suggested that p-glycoprotein reach full mature levels at approximately two weeks of age [158]. While these finding help guide us to the cause of toxicity, all of these studies only measured the mRNA levels and not protein expression.…”

Section: Preclinical Considerationsmentioning

confidence: 99%

“…Surprisingly this is often overlooked in preclinical and clinical trials. Typically the clinic has treated children as small adults with dose levels adjusted only based on body weight or surface area [158]. This approach fails to recognize the different developmental stages and can be lead to toxicity.…”

Section: Preclinical Considerationsmentioning

confidence: 99%

“…Decreased expression of organic cation transporter 1 could result in a slow elimination of the drug and thus increase exposure of carboplatin. The other transporters, multidrug resistance protein 2 and copper transporter, are also expressed at levels that are greater than adult and may, theoretically, compensate for the lack of organic transporter 1 elimination [158]. In addition, it is necessary to consider the transporters for topotecan, since both drugs are given at the same time.…”

Section: Preclinical Considerationsmentioning

confidence: 99%

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