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Prediction of total propofol clearance based on enzyme activities in microsomes from human kidney and liver

  • Pharmacokinetics and Disposition
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Abstract

Objective

Propofol is commonly used for anesthesia and sedation in intensive care units. Approximately 53% of injected propofol is excreted in the urine as the glucuronide and 38% as hydroxylated metabolites. Liver, kidneys and intestine are suspected as clearance tissues. We investigated the contribution of the liver and kidneys to propofol metabolism in humans using an in vitro–in vivo scale up approach.

Methods

Renal tissue was obtained from five patients who received nephrectomies. Each renal hydroxylation and glucuronidation enzymatic activities in microsomal fractions from patients were performed discretely and their estimation based on the decrease of propofol concentration. Hepatic hydroxylation and glucuronidation activities were also performed separately using human liver microsomes. This estimation is based on the decrease of propofol concentration, assuming that the contribution of hydroxylation activity without NADPH-generating system and glucuronidation activity without UDPGA in each microsomal fraction are negligible. Both renal and hepatic clearances were estimated assuming a well-stirred model.

Results

Enzymatic activity of propofol oxidation in renal microsomes was negligible. Although glucuronidation activity in microsomes from kidneys was comparable to that from liver, the hepatic intrinsic clearance predicted from in vitro study was higher than that in kidneys due to the larger tissue volume and higher protein concentration. However, glucuronidation clearance in kidney is relatively similar to that in liver because of blood flow limitation of clearance in both tissues.

Conclusion

The high degree of hydroxylation activity in liver microsomes is consistent with the blood flow-limited hepatic clearance of propofol. Although the activity of propofol glucuronidation in liver is higher, glucuronidation in kidney may be a substantial contributor.

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Acknowledgements

We thank Daisuke Yoshikawa, MD, PhD, and Daisuke Takizawa, MD, for their technical assistance. The experiments comply with the current law of the country in which they were performed inclusive of ethics approval. Financial support was provided solely from institutional and/or departmental sources.

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Authors and Affiliations

  1. Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Wael S. Al-Jahdari, Haruhiko Hiraoka & Fumio Goto

  2. Department of Clinical Pharmacology, Gunma University Graduate school of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Wael S. Al-Jahdari, Koujirou Yamamoto, Haruhiko Hiraoka, Katsunori Nakamura & Ryuya Horiuchi

Authors
  1. Wael S. Al-Jahdari
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  2. Koujirou Yamamoto
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  3. Haruhiko Hiraoka
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  4. Katsunori Nakamura
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  5. Fumio Goto
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  6. Ryuya Horiuchi
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Correspondence to Ryuya Horiuchi.

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Al-Jahdari, W.S., Yamamoto, K., Hiraoka, H. et al. Prediction of total propofol clearance based on enzyme activities in microsomes from human kidney and liver. Eur J Clin Pharmacol 62, 527–533 (2006). https://doi.org/10.1007/s00228-006-0130-2

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  • DOI: https://doi.org/10.1007/s00228-006-0130-2

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