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Current Drug Metabolism

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ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

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Short Communication

Effects of Clarithromycin and Ketoconazole on FK506 Metabolism in Different CYP3A4 Genotype Recombinant Metabolic Enzyme Systems

Author(s): Jinhua Wen*, Yuwei Xiao, Menghua Zhao, Chen Yang and Weiqiang Hu

Volume 25, Issue 2, 2024

Published on: 20 March, 2024

Page: [174 - 177] Pages: 4

DOI: 10.2174/0113892002286019240315052145

Price: $65

Abstract

Objective: This study aimed to investigate the effects of clarithromycin and ketoconazole on the pharmacokinetic properties of tacrolimus in different CYP3A4 genotype recombinant metabolic enzyme systems, so as to understand the drug interactions and their mechanisms further.

Method: The experiment was divided into three groups: a blank control group, CYP3A4*1 group and CYP3A4*18 recombinant enzyme group. Each group was added with tacrolimus (FK506) of a series of concentrations. Then 1 umol/L clarithromycin or ketoconazole was added to the recombinant enzyme group and incubated in the NADPH system for 30 minutes to examine the effects of clarithromycin and ketoconazole on the metabolizing enzymes’ activity of different genotypes. The remaining concentration of FK506 in the reaction system was determined using UPLC-MS/MS, and the enzyme kinetic parameters were calculated using the software.

Results: The metabolism of CYP3A4*18 to FK506 was greater than that of CyP3А4*1B. Compared with the CYP3A4*1 group, the metabolic rate and clearance of FK506 in the CYP3A4*18 group significantly increased, with Km decreasing. Clarithromycin and ketoconazole inhibit the metabolism of FK506 by affecting the enzyme activity of CYP3A4*1B and CYP3A4*18B. After adding clarithromycin or ketoconazole, the metabolic rate of FK506 significantly decreased in CYP3A4*1 and CYP3A4*18, with Km increasing, Vmax and Clint decreasing.

Conclusion: Compared with CYP3A4*1, CYP3A4*18 has a greater metabolism of FK506, clarithromycin and ketoconazole can inhibit both the enzymatic activities of CYP3A4*1 and CYP3A4*18, consequently affecting the metabolism of FK506 and the inhibitory on CYP3A4*1 is stronger.

Keywords: clarithromycin, CYP3A4, tacrolimus, ketoconazole, CYP3A4*1B, CYP3A4*18B.

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[1]
Munda, R.; Alexander, J.W.; First, M.R.; Gartside, P.S.; Fidler, J.P. Pulmonary infections in renal transplant recipients. Ann. Surg., 1978, 187(2), 126-133.
[http://dx.doi.org/10.1097/00000658-197802000-00005] [PMID: 343733]
[2]
Cheng, S.; Tang, M.; Du, J.; Yin, T. Effects of antifungal drugs on the plasma concentrations and dosage of tacrolimus in kidney transplant patients. Eur. J. Hosp. Pharm. Sci. Pract., 2022, 29(4), 202-206.
[http://dx.doi.org/10.1136/ejhpharm-2020-002385] [PMID: 33020057]
[3]
Rivosecchi, R.M.; Clancy, C.J.; Shields, R.K.; Ensor, C.R.; Shullo, M.A.; Falcione, B.A.; Venkataramanan, R.; Nguyen, M.H. Effects of isavuconazole on the plasma concentrations of tacrolimus among solid-organ transplant patients. Antimicrob. Agents Chemother., 2017, 61(9), e00970-17.
[http://dx.doi.org/10.1128/AAC.00970-17] [PMID: 28674051]
[4]
Kirubakaran, R.; Stocker, S.L.; Hennig, S.; Day, R.O.; Carland, J.E. Population pharmacokinetic models of tacrolimus in adult transplant recipients: A systematic review. Clin. Pharmacokinet., 2020, 59(11), 1357-1392.
[http://dx.doi.org/10.1007/s40262-020-00922-x] [PMID: 32783100]
[5]
Liu, J.; Chen, D.; Yao, B.; Guan, G.; Liu, C.; Jin, X.; Wang, X.; Liu, P.; Sun, Y.; Zang, Y. Effects of donor–recipient combinational CYP3A5 genotypes on tacrolimus dosing in Chinese DDLT adult recipients. Int. Immunopharmacol., 2020, 80, 106188.
[http://dx.doi.org/10.1016/j.intimp.2020.106188] [PMID: 31931373]
[6]
Rodriguez-Antona, C.; Savieo, J.L.; Lauschke, V.M.; Sangkuhl, K.; Drögemöller, B.I.; Wang, D.; van Schaik, R.H.N.; Gilep, A.A.; Peter, A.P.; Boone, E.C.; Ramey, B.E.; Klein, T.E.; Whirl-Carrillo, M.; Pratt, V.M.; Gaedigk, A. PharmVar GeneFocus: CYP3A5. Clin. Pharmacol. Ther., 2022, 112(6), 1159-1171.
[http://dx.doi.org/10.1002/cpt.2563] [PMID: 35202484]
[7]
Qi, G.; Han, C.; Zhou, Y.; Wang, X. Allele and genotype frequencies of CYP3A4, CYP3A5, CYP3A7, and GSTP1 gene polymorphisms among mainland Tibetan, Mongolian, Uyghur, and Han Chinese populations. Clin. Exp. Pharmacol. Physiol., 2022, 49(2), 219-227.
[http://dx.doi.org/10.1111/1440-1681.13604] [PMID: 34689350]
[8]
Hesselink, D.; van Schaik, R.H.N.; van der Heiden, I.P.; van der Werf, M.; Gregoor, P.J.H.S.; Lindemans, J.; Weimar, W.; van Gelder, T. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin. Pharmacol. Ther., 2003, 74(3), 245-254.
[http://dx.doi.org/10.1016/S0009-9236(03)00168-1] [PMID: 12966368]
[9]
Fukushima-Uesaka, H.; Saito, Y.; Watanabe, H.; Shiseki, K.; Saeki, M.; Nakamura, T.; Kurose, K.; Sai, K.; Komamura, K.; Ueno, K.; Kamakura, S.; Kitakaze, M.; Hanai, S.; Nakajima, T.; Matsumoto, K.; Saito, H.; Goto, Y.; Kimura, H.; Katoh, M.; Sugai, K.; Minami, N.; Shirao, K.; Tamura, T.; Yamamoto, N.; Minami, H.; Ohtsu, A.; Yoshida, T.; Saijo, N.; Kitamura, Y.; Kamatani, N.; Ozawa, S.; Sawada, J. Haplotypes ofCYP3A4 and their close linkage withCYP3A5 haplotypes in a Japanese population. Hum. Mutat., 2004, 23(1), 100.
[http://dx.doi.org/10.1002/humu.9210] [PMID: 14695543]
[10]
Shi, X.J.; Geng, F.; Jiao, Z.; Cui, X.Y.; Qiu, X.Y.; Zhong, M.K. Association of ABCB1, CYP3A4*18B and CYP3A5*3 genotypes with the pharmacokinetics of tacrolimus in healthy Chinese subjects: a population pharmacokinetic analysis. J. Clin. Pharm. Ther., 2011, 36(5), 614-624.
[http://dx.doi.org/10.1111/j.1365-2710.2010.01206.x] [PMID: 21916909]
[11]
Hu, Y.F.; Tu, J.H.; Tan, Z.R.; Liu, Z.Q.; Zhou, G.; He, J.; Wang, D.; Zhou, H.H. Association of CYP3A4*18B polymorphisms with the pharmacokinetics of cyclosporine in healthy subjects. Xenobiotica, 2007, 37(3), 315-327.
[http://dx.doi.org/10.1080/00498250601149206] [PMID: 17624028]
[12]
Qiu, X.; Jiao, Z.; Zhang, M.; Zhong, L.; Liang, H.; Ma, C.; Zhang, L.; Zhong, M. Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients. Eur. J. Clin. Pharmacol., 2008, 64(11), 1069-1084.
[http://dx.doi.org/10.1007/s00228-008-0520-8] [PMID: 18636247]
[13]
Li, Y.; Yan, L.; Shi, Y.; Bai, Y.; Tang, J.; Wang, L. CYP3A5 and ABCB1 genotype influence tacrolimus and sirolimus pharmacokinetics in renal transplant recipients. Springerplus, 2015, 4(1), 637.
[http://dx.doi.org/10.1186/s40064-015-1425-5] [PMID: 26543771]

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