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Interplay of UDP-Glucuronosyltransferase and CYP2C8 for CYP2C8 Mediated Drug Oxidation and Its Impact on Drug–Drug Interaction Produced by Standardized CYP2C8 Inhibitors, Clopidogrel and Gemfibrozil

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Abstract

Background and Objective

Early investigations into drug–drug interactions (DDIs) involving cytochrome P450 2C8 (CYP2C8) have highlighted the complexity of interactions between CYP2C8 substrate drugs, including montelukast, desloratadine, pioglitazone, repaglinide, and cerivastatin (the latter two being OATP1B1 substrates), and standardized CYP2C8 inhibitors such as clopidogrel (Clop) and gemfibrozil (Gem). These interactions have proven challenging to predict based solely on simple CYP inhibition. A hypothesis has emerged suggesting that these substrate drugs first distribute to UDP-glucuronosyltransferase (UGT) before undergoing oxidation by CYP2C8, resulting in bidirectional elimination. The process of drug distribution to UGT is believed to significantly impact these DDIs. This study aims to explore the intricate interplay between UGT and CYP2C8 in the context of DDIs involving CYP2C8 substrates affected by Clop and Gem.

Methods

Plasma-level data for the unchanged drug and its metabolite, drawn from the respective literature, formed the basis of our analysis. We evaluated the enzymatic inhibitory activities of DDIs and utilized simulations to estimate plasma levels of the unchanged victim drug and its metabolite in each DDI. This was accomplished by employing a functional relationship that considered the fractional contributions of CYP2C8 and UGT to clearance, perpetrator-specific inhibitory activities against CYP2C8, and drug distribution to UGT.

Results

Our findings emphasize the pivotal role of UGT-mediated distribution in the context of CYP2C8 substrate metabolism, particularly in the complex DDIs induced by Clop and Gem. In these DDIs, Gem exerts inhibitory effects on both UGT and CYP2C8, whereas Clop (specifically its metabolite, Clop-COOH) solely targets CYP2C8. Importantly, the inhibition of CYP2C8 by both Clop and Gem is achieved through a non-competitive mechanism, driven by the actions of their acyl-glucuronides. Clop and Gem exhibit inhibition activities accounting for 85% (pAi,CYP2C8 = 7) and 93% (pAi,CYP2C8 = 15), respectively. In contrast, Gem's inhibition of UGT is relatively modest (50%, pAi,UGT(d) = 2), and it operates through a non-specific, competitive process in drug distribution to UGT. Within this context, our UGT-CYP2C8 interplay model offers an accurate means of predicting the alterations resulting from DDIs, encompassing changes in plasma levels of the unchanged drug and its metabolites, as well as shifts in metabolite formation rates. Our analysis highlights the critical importance of considering the fractional contributions of CYP2C8 and UGT to the victim drug's clearance (fm,CYP2C8; fm,UGT) in DDI prediction. Furthermore, our examination of DDIs involving OATP1B1 substrate drugs underscores that accounting for the hepatic uptake transporters' role in the liver is superfluous in DDI prediction.

Conclusion

These findings substantially enhance our comprehension of CYP2C8-mediated oxidation and DDIs, holding crucial implications for drug development and the planning of clinical trials involving these inhibitors.

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Acknowledgements

We acknowledge the existence of a preprint version, available on Research Square (https://assets.researchsquare.com/files/rs-2364592/v1_coveres.pdf?c=1673300686), which shares a 39% overlap with this manuscript. The preprint has not undergone peer review.

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Authors and Affiliations

  1. Pharmaceutical Research and Technology Unit, R & D Division, Pre-formulation Department, Towa Pharmaceutical Co., Ltd, Kyoto Research Park KISTIC #202, 134, Chudoji Minami-machi, Shimogyo-ku, Kyoto, 600-8813, Japan

    Katsumi Iga

  2. Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kodo Kyotanabe-shi, Kyoto, 610-0395, Japan

    Akiko Kiriyama

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  1. Katsumi Iga
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Correspondence to Katsumi Iga.

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KI and AK declare that they have no conflict of interest.

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Additional data are given in the electronic supplementary material.

Author’s Contributions

KI contributed to the study conception and design. Data collection and analysis were performed by KI and AK. The first draft of the manuscript was written by KI, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Iga, K., Kiriyama, A. Interplay of UDP-Glucuronosyltransferase and CYP2C8 for CYP2C8 Mediated Drug Oxidation and Its Impact on Drug–Drug Interaction Produced by Standardized CYP2C8 Inhibitors, Clopidogrel and Gemfibrozil. Clin Pharmacokinet 63, 43–56 (2024). https://doi.org/10.1007/s40262-023-01322-7

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