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Contribution of rat intestinal metabolism to the xenobiotics clearance

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Abstract

Michaelis–Menten constants K m and V max values were determined by product formation and substrate depletion at several substrate concentrations of 4-methylumbelliferone using rat intestinal microsomes. K m and V max values determined by measuring product formation were in good agreement with substrate depletion approach. We also investigated hepatic and intestinal in vitro intrinsic clearance (CLint) in the liver and intestinal microsomes and compare with reports in the literature using nine test compounds, atorvastatin, 7-ethoxycoumarin, indomethacin, 4-methylumbelliferone, midazolam, nifedipine, testosterone, terfenadine and verapamil, in rats. CLint was determined from the substrate disappearance rate at 0.1 and 0.5 μM in the rat intestinal and liver microsomes, respectively. These results showed that both the liver and the intestine contributed to the metabolism of these compounds. The intestinal intrinsic clearance values of all these drugs, except for terfenadine in the rat intestinal microsomes, were lower than their hepatic intrinsic clearance per milligram protein, showing that there was an organ difference in metabolism between the liver and intestinal. These results make the evaluation using the intestinal more useful and provide a basis for predicting clearance using intestinal.

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Abbreviations

EDTA:

Ethylenediaminetetraacetic acid

CLint :

Intrinsic clearance

NADPH:

β-Nicotinamide adenine dinucleotide phosphate

UPLC–MS/MS:

Ultraperformance liquid chromatography–tandem mass spectrometry

UGT:

UDP-glucuronosyltransferase

UDPGA:

Uridine diphosphate-glucuronic acid

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Authors and Affiliations

  1. Bioanalytics, Metabolism and in vitro Technologies, DMPK, Aptuit, Via A. Fleming, 4, 37135, Verona, Italy

    Mahmud Kajbaf, Raffaella Ricci, Serenella Zambon & Stefano Fontana

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  1. Mahmud Kajbaf
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  2. Raffaella Ricci
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  3. Serenella Zambon
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  4. Stefano Fontana
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Correspondence to Mahmud Kajbaf.

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Kajbaf, M., Ricci, R., Zambon, S. et al. Contribution of rat intestinal metabolism to the xenobiotics clearance. Eur J Drug Metab Pharmacokinet 38, 33–41 (2013). https://doi.org/10.1007/s13318-012-0098-5

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  • DOI: https://doi.org/10.1007/s13318-012-0098-5

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