Age-related changes in hepatic expression and activity of cytochrome P450 in male rats

Yun, Kang Uk; Oh, Soo Jin; Oh, Jung Min; Kang, Keon Wook; Myung, Chang‐Seon; Song, Gyu Yong; Kim, Bong-Hee; Kim, Sang Kyum

doi:10.1007/s00204-010-0520-1

Cited by 53 publications

(62 citation statements)

References 27 publications

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“…CYP2B expression changes through development; early adolescent rats had higher levels of hepatic CYP2B protein compared with adults (Yun et al, 2010). However, our data do not support a faster conversion of nicotine to cotinine in the early adolescent cohort, as both nicotine and cotinine levels are lower.…”

Section: Discussioncontrasting

confidence: 81%

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: Discussioncontrasting

confidence: 81%

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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“…37 These changes may be the result of increased blood flow throughout the body or increased expression of some CYPs in the liver, as observed for CYP2Cs, CYP2Bs, and CYP1A proteins in our study. Moreover, although CYP1A2 protein levels have been shown to decrease with aging, 38 we found that CYP1A protein levels were increased in the swimming exercise group compared with the control group.…”

Section: Discussioncontrasting

confidence: 64%

“…38 For example, CYP1A2, CYP2B1, and CYP2E1 levels were increased in 3-week-old rats compared with those in 12-, 26-, and 104 week-old rats. Moreover, CYP2C11 and CYP3A2 expression has been shown to decrease with age.…”

Section: Discussionmentioning

confidence: 88%

Expression Profiles of Cytochrome P450s Following Swimming Exercise in Aging Rats

Lee¹,

So²,

Kim³

et al. 2017

JOMH

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“…Some variations within groups regarding uptake of radioactivity in the liver (Fig. 3C) might be explained by age-related differences in biodistribution related to changes in enzyme activity and isoform distributions during aging, as reported in several studies (28)(29)(30).…”

Section: Discussionsupporting

confidence: 55%

Metabolism of Epidermal Growth Factor Receptor Targeting Probe [¹¹C]PD153035: Impact on Biodistribution and Tumor Uptake in Rats

Samén

Arnberg

et al. 2013

J Nucl Med

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Several tracers have been evaluated as probes for noninvasive epidermal growth factor receptor (EGFR) quantification with PET. One of the most promising candidates is the 11 C-labeled analog of the EGFR tyrosine kinase inhibitor PD153035. However, previous in vitro studies indicated extensive metabolism of the tracer, which could be disadvantageous for the assessment of receptor density in vivo. The aim of this study was to investigate the in vivo metabolism of [ 11 C]PD153035 to determine whether alterations in metabolite formation are accompanied by changes in biodistribution and tumor uptake. Methods: EGFR-overexpressing human epidermoid carcinoma xenografts in rats were used in all examinations of tumor uptake. Cytochrome P450 enzymes of subfamilies CYP2D and CYP3A were inhibited before intravenous injection of [ 11 C] PD153035 into healthy and tumor-bearing male rats. Samples were taken from arterial blood and urine, and the occurrence of radioactive metabolites was assessed with radio-high-performance liquid chromatography. Dynamic PET examinations of healthy and tumorbearing animals were performed. In 1 rat, the effect of local intraarterial administration was examined. Results: [ 11 C]PD153035 labeled at position 6 was metabolized extensively in vivo in male rats, resulting in very low levels of the intact tracer in plasma only minutes after injection. The major identified radiolabeled metabolites found were the N-oxide and metabolites arising from O demethylation at position 7. They were reduced by inhibition of CYP2D and CYP3A enzymes. PET revealed enzyme activity-dependent changes in the radioactivity distribution in the liver and tumors. Local administration of [ 11 C]PD153035 greatly increased radioactivity levels in the adjacent tumor compared with levels typically found after intravenous administration. The highest tumor-to-muscle ratio at 60 min after intravenous injection was found in the untreated animals, whereas the overall highest ratio was found in the tumor near the intraarterial administration site. Conclusion: We suggest that the metabolism of [ 11 C]PD153035 should be taken into consideration when this tracer is used to quantify EGFR expression, as our results indicated that the distribution of radioactivity to EGFR-overexpressing tumors was affected by the rate of metabolism and the route of administration.Key Words: PET; epidermal growth factor receptor; metabolism; The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases. Overexpression of EGFR and its cognate ligands has been shown to contribute to increased proliferation and invasiveness of several tumor types (1). The intracellular portion of the EGFR consists of a tyrosine kinase domain that is activated by ligand binding and receptor dimerization and is a potential therapeutic target for the group of drugs known as tyrosine kinase inhibitors (TKIs). These drugs act by inhibiting the adenosine triphosphate-binding site of tyrosine kinase and thereby blocking subsequent diverse intracellu...

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Age-related changes in hepatic expression and activity of cytochrome P450 in male rats

Cited by 53 publications

References 27 publications

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

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

Expression Profiles of Cytochrome P450s Following Swimming Exercise in Aging Rats

Metabolism of Epidermal Growth Factor Receptor Targeting Probe [¹¹C]PD153035: Impact on Biodistribution and Tumor Uptake in Rats

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Age-related changes in hepatic expression and activity of cytochrome P450 in male rats

Cited by 53 publications

References 27 publications

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

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

Expression Profiles of Cytochrome P450s Following Swimming Exercise in Aging Rats

Metabolism of Epidermal Growth Factor Receptor Targeting Probe [11C]PD153035: Impact on Biodistribution and Tumor Uptake in Rats

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Metabolism of Epidermal Growth Factor Receptor Targeting Probe [¹¹C]PD153035: Impact on Biodistribution and Tumor Uptake in Rats