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Lack of strain-related differences in drug metabolism and efflux transporter characteristics between CD-1 and athymic nude mice

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Abstract

CD-1 mice are commonly used in oncology metabolism and toxicity to support drug discovery and development and to examine drug metabolism and toxicity properties of new chemical entities. On the other hand, athymic nude mice are the preferred animals to investigate tumor growth inhibition. Therefore, a frequently asked question is: are the metabolic and pharmacokinetic characteristics of xenobiotics in these two mouse strains comparable or not? To address this issue, we characterized drug metabolism and efflux transporter properties in both strains and in different organs. The metabolic stability of a set of 20 compounds and metabolite formation of cytochrome P450 (CYP) marker substrates (testosterone, ethoxyresorufin and pentoxyresorufin) were measured in liver microsomes. Drug conjugation was studied by following the disappearance of 7-hydroxycoumarin and the formation of its glucuronide and sulfate conjugates in freshly prepared liver slices. In addition, mRNA expression levels of the main cyp genes and drug efflux transporters were investigated by real-time RT-PCR in the liver, kidney, intestine and adrenal glands. No significant differences in enzymatic activities and metabolite formation were observed between the two strains. Also mRNA expression profiles of cyp and drug transporter genes were similar between CD-1 and nude mice.

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Abbreviations

BSA:

Bovine serum albumin

CLint:

Intrinsic metabolic clearance

CYP:

Cytochrome P450

DMSO:

Dimethylsulfoxide

dATP:

2′-Deoxyadenine 5′-triphosphate

dCTP:

2′-Deoxycytosine 5′-triphosphate

dGTP:

2′-Deoxyguanine 5′-triphosphate

dNTP:

2′-Deoxynucleoside 5′-triphosphate

dTTP:

2′-Deoxythymine 5′-triphosphate

EROD:

7-Ethoxyresorufin-O-deethylase

7-HC:

7-Hydroxycoumarin

LPS:

Lipopolysaccharide

mdr1a/1b:

Multidrug resistance 1a/1b

mrp1/2:

Multidrug resistance associated protein 1/2

LC–MS/MS:

Liquid chromatography coupled to tandem mass spectrometry

[S]:

Substrate concentration

PROD:

7-Pentoxyresorufin-O-depenthylase

TOH:

Testosterone hydroxylase

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Acknowledgement

The authors are grateful to Dr. Peter Buchan for critical reading of the manuscript.

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Authors and Affiliations

  1. Pharmacokinetics, Dynamics and Metabolism, Pharmacia Italy, Pfizer Group, Inc., Viale Pasteur 10, 20014, Nerviano, MI, Italy

    Marcella Martignoni, Ruben de Kanter, Anna Moscone, Pietro Grossi & Mario Monshouwer

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  1. Marcella Martignoni
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  2. Ruben de Kanter
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  3. Anna Moscone
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  4. Pietro Grossi
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  5. Mario Monshouwer
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Correspondence to Marcella Martignoni.

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Martignoni, M., de Kanter, R., Moscone, A. et al. Lack of strain-related differences in drug metabolism and efflux transporter characteristics between CD-1 and athymic nude mice. Cancer Chemother Pharmacol 55, 129–135 (2005). https://doi.org/10.1007/s00280-004-0898-7

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  • DOI: https://doi.org/10.1007/s00280-004-0898-7

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