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Effect of UGT1A1, CYP3A and CES Activities on the Pharmacokinetics of Irinotecan and its Metabolites in Patients with UGT1A1 Gene Polymorphisms

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Abstract

Background and Objectives

Irinotecan (CPT-11) is metabolized to an active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterase (CES). SN-38 is then converted to the inactive metabolite SN-38 glucuronide (SN-38G) by glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphisms in UGT1A1 have been associated with altered SN-38 pharmacokinetics, which increase the risk of toxicity in patients. CPT-11 is also converted to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC) by cytochrome P450 3A (CYP3A), and this route also affects the plasma concentration of SN-38. We evaluated the activities of UGT1A1, CYP3A, and CES and the factors affecting the pharmacokinetics of plasma SN-38 in patients with UGT1A1 gene polymorphisms.

Methods

Three male patients aged 56, 65, and 49 years were recruited for the analysis. All patients had pancreatic cancer, received FOLFIRINOX, and had UGT1A1*6/*6 (patients 1 and 3) or *6/*28 (patient 2) genetic polymorphisms. The rate constants for evaluating the enzyme activity were determined from the measured plasma concentration of CPT-11 and its metabolites using a two-compartment model by WinNonlin.

Results

The area under the plasma concentration–time curve (AUC) of SN-38 was patient 1 > patient 2 > patient 3. The rate constants obtained from the model analysis indicated the respective enzyme activities of UGT1A1 (k57), CYP3A (k13 + k19), and CES (k15). The order of values for UGT1A1 activity was patient 2 > patient 3 > patient 1. Since UGT1A1 activity was low in patient 1 with a high AUC of SN-38, it can be said that the increase in plasma concentration was due to a decrease in UGT1A1 activity. Conversely, the order of values for CYP3A and CES activities was patient 3 > patient 1 > patient 2 and patient 2 > patient 1 > patient 3, respectively. Patient 3 had the lowest AUC of SN-38, caused by a lower level of CES activity and increased CYP3A activity.

Conclusion

In this study, we indicated that the plasma AUC of SN-38 and AUC ratio of SN-38G/SN-38 may depend on changes in the activities of CYP3A, CES, and UGT1A1. Using pharmacokinetic analysis, it is possible to directly evaluate enzyme activity and consider what kind of enzyme variation causes the increase in the AUC of SN-38.

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Authors and Affiliations

  1. Department of Clinical Pharmacy and Experimental Therapeutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan

    Akitomo Yokokawa, Shun Kaneko, Sayuri Endo, Yuki Minowa, Hideaki Ayukawa, Ryohei Hirano, Takashi Furuta & Hiromi Shibasaki

  2. Department of Medical Oncology, Faculty of Medicine, Kyorin University, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan

    Fumio Nagashima, Daisuke Naruge, Naohiro Okano, Takaaki Kobayashi, Kirio Kawai & Junji Furuse

Authors
  1. Akitomo Yokokawa
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  2. Shun Kaneko
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  3. Sayuri Endo
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  4. Yuki Minowa
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  5. Hideaki Ayukawa
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  6. Ryohei Hirano
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  7. Fumio Nagashima
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  8. Daisuke Naruge
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  9. Naohiro Okano
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  10. Takaaki Kobayashi
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  11. Kirio Kawai
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  12. Junji Furuse
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  13. Takashi Furuta
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  14. Hiromi Shibasaki
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Corresponding author

Correspondence to Akitomo Yokokawa.

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Funding

No source of funding.

Conflicts of interest

Fumio Nagashima received personal fees from Taiho, Chugai, Yakult, Sumitomo Dainippon, Merck Serono, Takeda, Kyowa Hakko Kirin, Sanofi Mochida, Janssen and Nestle. Naohiro Okano received personal fees from Merck Serono, Taiho, Eisai and J-Pharma. Junji Furuse received grants from J-Pharma, Taiho, Sumitomo Dainippon, Janssen, Daiichi Sankyo, MSD, Yakult, Takeda, Chugai, Ono, Astellas, Zeria, Novartis, Nanocarrier, Shionogi, Onco Therapy Science, Eli Lilly Japan, Bayer, Bristol-Myers Squibb, Merck Serono, Kyowa Hakko Kirin, Eisai, NanoCarrier, Mochida, Baxalta and Sanofi, and received personal fees from Taiho, Chugai, Yakult, Sumitomo Dainippon, Eli Lilly Japan, Astellas, Ono, Pfizer, Bayer, Novartis, Merck Serono, Takeda, Eisai, MSD, Shionogi, J-Pharma, Daiichi Sankyo, Kyowa Hakko Kirin, Sanofi, Sandoz, Otsuka, Zeria, Fujifilm, Astra Zeneca, Asahi Kasei, Shire, Mochida, Nippon Kayaku, EA pharma, Sawai and Teijin Pharma. CPT-11, SN-38, SN-38G and APC were kindly donated by Yakult Honsha.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments. The study was approved by Kyorin University Faculty of Medicine and Tokyo University of Pharmacy and Life Sciences Human Subjects Review Board.

Informed consent

Written informed consent was obtained from all patients participating in the study.

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Yokokawa, A., Kaneko, S., Endo, S. et al. Effect of UGT1A1, CYP3A and CES Activities on the Pharmacokinetics of Irinotecan and its Metabolites in Patients with UGT1A1 Gene Polymorphisms. Eur J Drug Metab Pharmacokinet 46, 317–324 (2021). https://doi.org/10.1007/s13318-021-00675-3

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  • DOI: https://doi.org/10.1007/s13318-021-00675-3

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