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Effect of chronic hypoxic hypoxia on oxidation and glucuronidation of carvedilol in rats

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Abstract

Heart failure is accompanied with tissue (circulatory) hypoxia, and the metabolism of several drugs has been reported to be reduced in heart failure. The aim of this study was to investigate the effect of another type of respiratory hypoxia, hypoxic hypoxia (FiO2 15 % for 24 h followed by FiO2 10 % for 9 days) on the metabolism of carvedilol enantiomers in rats. Oxidation of carvedilol in rat liver microsomes was evaluated in the presence of reduced nicotinamide adenine dinucleotide phosphate, whereas glucuronidation was evaluated in the presence of UDP-glucuronic acid. Both oxidation and glucuronidation activities for two carvedilol enantiomers in hypoxic rat liver microsomes were similar to those in control rat liver microsomes. We also performed pharmacokinetic analysis of carvedilol enantiomers following intraportal infusion in control and hypoxic rats. The mean (±S.E.) portal clearance value of R- and S-carvedilol in control rats was 72 ± 16 and 156 ± 31 ml/min/kg, respectively, whereas that of the R- and S-enantiomers in hypoxic rats was 68 ± 8 and 113 ± 14 ml/min/kg, respectively. These findings indicated that the metabolism of carvedilol enantiomers was not significantly diminished in rats with chronic hypoxic hypoxia, and that other factor(s) besides hypoxia may be responsible for the reduced drug metabolism in heart failure.

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Acknowledgments

This work was supported in part by Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Sciences (JSPS).

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Authors and Affiliations

  1. Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Shizuka Yamaura, Miki Fukao, Kazuya Ishida, Masato Taguchi & Yukiya Hashimoto

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  1. Shizuka Yamaura
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  2. Miki Fukao
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  3. Kazuya Ishida
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  4. Masato Taguchi
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  5. Yukiya Hashimoto
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Correspondence to Yukiya Hashimoto.

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Yamaura, S., Fukao, M., Ishida, K. et al. Effect of chronic hypoxic hypoxia on oxidation and glucuronidation of carvedilol in rats. Eur J Drug Metab Pharmacokinet 39, 53–59 (2014). https://doi.org/10.1007/s13318-013-0140-2

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  • DOI: https://doi.org/10.1007/s13318-013-0140-2

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