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Examining Physiologically-Based Pharmacokinetic (PBPK) Model Assumptions for Cross-Tissue Similarity of Kcat: The Case Example of Uridine 5'-diphosphate Glucuronosyltransferase (UGT)

Anika N Ahmed, Amin Rostami-Hodjegan, Jill Barber and Zubida M. Al-Majdoub
Drug Metabolism and Disposition May 30, 2022, DMD-COM-2021-000813; DOI: https://doi.org/10.1124/dmd.121.000813
Anika N Ahmed
1Centre for Applied Pharmacokinetic Research,, The University of Manchester, United Kingdom
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Amin Rostami-Hodjegan
2Systems Pharmacology, Manchester Pharmacy School, University of Manchester, United Kingdom
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Jill Barber
3Pharmacy and Pharmaceutical Sciences, University of Manchester, United Kingdom
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Zubida M. Al-Majdoub
4Division of Pharmacy and Optometry, University of Manchester, United Kingdom
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  • ORCID record for Zubida M. Al-Majdoub
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Abstract

The default assumption during in vitro in vivo extrapolation (IVIVE) to predict metabolic clearance in physiologically-based pharmacokinetics (PBPK) is that protein expression and activity have the same relationship in various tissues. This assumption is examined for uridine 5'-diphosphate glucuronosyltransferases (UGTs), a case example where expression and, hence, metabolic activity are distributed across various tissues. Our literature analysis presents overwhelming evidence of a greater UGT activity per unit of enzyme (higher kcat) in kidney and intestinal tissues relative to liver (greater than 200-fold for UGT2B7). This analysis is based on application of abundance values reported using similar proteomic techniques and within the same laboratory. Our findings call into question the practice of assuming similar kcat during IVIVE estimations as part of PBPK, and call for a systematic assessment of the kcat of various enzymes across different organs. The analysis focused on compiling data for probe substrates that were common for two or more of the studied tissues, to allow for reliable comparison of cross-tissue enzyme kinetics; this meant that UGT enzymes included in the study were limited to UGT1A1, 1A3, 1A6, 1A9 and 2B7. Significantly, UGT1A9 (n=24) and the liver (n=27) were each found to account for around half of the total dataset; these were found to correlate, with hepatic UGT1A9 data found in 15 of the studies, highlighting the need for more research into extrahepatic tissues and other UGT isoforms.

Significance Statement During PBPK modelling (in vitro in vivo extrapolation) of drug clearance, the default assumption is that the activity per unit of enzyme (kcat) is the same in all tissues. The analysis provides preliminary evidence that this may not be the case, and that renal and intestinal tissues may have almost 250-fold greater UGT activity per unit of enzyme than liver tissues.

  • drug metabolism
  • gastrointestinal tract
  • glucuronidation/UDP-glucuronyltransferases/UGT
  • in vitro-in vivo prediction (IVIVE)
  • kidney/renal
  • Liver
  • physiologically-based pharmacokinetic modeling/PBPK
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 51 (2)
Drug Metabolism and Disposition
Vol. 51, Issue 2
1 Feb 2023
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Kcat assessment of UGT enzymes across different organs.

Anika N Ahmed, Amin Rostami-Hodjegan, Jill Barber and Zubida M. Al-Majdoub
Drug Metabolism and Disposition May 30, 2022, DMD-COM-2021-000813; DOI: https://doi.org/10.1124/dmd.121.000813

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OtherCommentary

Kcat assessment of UGT enzymes across different organs.

Anika N Ahmed, Amin Rostami-Hodjegan, Jill Barber and Zubida M. Al-Majdoub
Drug Metabolism and Disposition May 30, 2022, DMD-COM-2021-000813; DOI: https://doi.org/10.1124/dmd.121.000813
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  • Clearance Models: The Case for Status Quo
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