Login Register Cart 0
Generic placeholder image

Current Drug Metabolism

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Functional Analysis of Wild-Type and 27 CYP3A4 Variants on Dronedarone Metabolism In vitro

Author(s): Chen-Chen Wang and Tian Lan*

Volume 23, Issue 7, 2022

Published on: 22 July, 2022

Page: [562 - 570] Pages: 9

DOI: 10.2174/1389200223666220613153917

Price: $65

Abstract

Background: Cytochrome P450 (P450) is the largest family of enzymatic proteins in the human liver, and its features have been studied in physiology, medicine, biotechnology, and phytoremediation.

Objective: The aim of this study was to assess the catalytic activities of 28 human CYP3A4 alleles by using dronedarone as a probe drug in vitro, including 7 novel alleles recently found in the Han Chinese population.

Methods: We expressed 28 CYP3A4 alleles in insect microsomes and incubated them with 1-100 μM of dronedarone at 37 °C for 40 minutes to obtain the metabolites of N-debutyl-dronedarone.

Results: Compared with the wild type of CYP3A4, the 27 defective alleles can be classified into four categories. Three alleles had no detectable enzyme activity leading to a lack of kinetic parameters of N-debutyl-dronedarone; the other three alleles slightly despaired when it comes to intrinsic clearance values compared with the features of the wild type. Sixteen alleles exhibited 35.91%~79.70% relative values (in comparison to the wild-type) and could be defined as the “moderate decrease group”. The rest of the alleles showed a considerable decrease in intrinsic clearance values, ranging from 11.88%~23.34%. Therefore they were classified as a “significantly decreased group”. More specifically, 18 CYP3A4 alleles exhibited a substrate inhibition trend toward dronedarone when the concentration rises to 20 μM.

Conclusion: The outcomes of this novel study on the metabolism of dronedarone by CYP3A4 alleles can be used as experimental data support for the individualized use of this modern drug.

Keywords: CYP3A4, genetic polymorphism, dronedarone, drug-metabolizing enzyme, intrinsic clearance, atrial fibrillation.

« Previous Next »
Graphical Abstract

[1]
Rasool, S.; Mohamed, R. Plant cytochrome P450s: Nomenclature and involvement in natural product biosynthesis. Protoplasma, 2016, 253(5), 1197-1209.
[http://dx.doi.org/10.1007/s00709-015-0884-4] [PMID: 26364028]
[2]
Lopez-Garcia, M.A.; Feria-Romero, I.A.; Serrano, H.; Rayo-Mares, D.; Fagiolino, P.; Vazquez, M.; Escamilla-Nunez, C.; Grijalva, I.; Es-calante-Santiago, D.; Orozco-Suarez, S. Influence of genetic variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A4 on antiepileptic drug me-tabolism in pediatric patients with refractory epilepsy. Pharmacol. Rep., 2017, 69(3), 504-511.
[http://dx.doi.org/10.1016/j.pharep.2017.01.007]
[3]
Drogemoller, B.; Plummer, M.; Korkie, L.; Agenbag, G.; Dunaiski, A.; Niehaus, D.; Koen, L.; Gebhardt, S.; Schneider, N.; Olckers, A.; Wright, G.; Warnich, L. Characterization of the genetic variation present in CYP3A4 in three South African populations. Front. Genet., 2013, 4, 17.
[http://dx.doi.org/10.3389/fgene.2013.00017]
[4]
Werk, A.N.; Lefeldt, S.; Bruckmueller, H.; Hemmrich-Stanisak, G.; Franke, A.; Roos, M.; Küchle, C.; Steubl, D.; Schmaderer, C.; Bräsen, J.H.; Heemann, U.; Cascorbi, I.; Renders, L. Identification and characterization of a defective CYP3A4 genotype in a kidney transplant patient with severely diminished tacrolimus clearance. Clin. Pharmacol. Ther., 2014, 95(4), 416-422.
[http://dx.doi.org/10.1038/clpt.2013.210] [PMID: 24126681]
[5]
Ohtsuki, S.; Schaefer, O.; Kawakami, H.; Inoue, T.; Liehner, S.; Saito, A.; Ishiguro, N.; Kishimoto, W.; Ludwig-Schwellinger, E.; Ebner, T.; Terasaki, T. Simultaneous absolute protein quantification of transporters, cytochromes P450, and UDP-glucuronosyltransferases as a novel approach for the characterization of individual human liver: Comparison with mRNA levels and activities. Drug Metab. Dispos., 2012, 40(1), 83-92.
[http://dx.doi.org/10.1124/dmd.111.042259] [PMID: 21994437]
[6]
Zanger, U.M.; Schwab, M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther., 2013, 138(1), 103-141.
[http://dx.doi.org/10.1016/j.pharmthera.2012.12.007] [PMID: 23333322]
[7]
Eiselt, R.; Domanski, T.L.; Zibat, A.; Mueller, R.; Presecan-Siedel, E.; Hustert, E.; Zanger, U.M.; Brockmoller, J.; Klenk, H.P.; Meyer, U.A.; Khan, K.K.; He, Y.A.; Halpert, J.R.; Wojnowski, L. Identification and functional characterization of eight CYP3A4 protein variants. Pharmacogenetics, 2001, 11(5), 447-458.
[http://dx.doi.org/10.1097/00008571-200107000-00008] [PMID: 11470997]
[8]
Tadros, R.; Nattel, S.; Andrade, J.G. Dronedarone: Basic pharmacology and clinical use. Card. Electrophysiol. Clin., 2016, 8(2), 453-465.
[http://dx.doi.org/10.1016/j.ccep.2016.02.008] [PMID: 27261834]
[9]
Klieber, S.; Arabeyre-Fabre, C.; Moliner, P.; Marti, E.; Mandray, M.; Ngo, R.; Ollier, C.; Brun, P.; Fabre, G. Identification of metabolic path-ways and enzyme systems involved in the in vitro human hepatic metabolism of dronedarone, a potent new oral antiarrhythmic drug. Pharmacol. Res. Perspect., 2014, 2(3), e00044.
[http://dx.doi.org/10.1002/prp2.44]
[10]
Zimetbaum, P.J. Dronedarone for atrial fibrillation-An odyssey. N. Engl. J. Med., 2009, 360(18), 1811-1813.
[http://dx.doi.org/10.1056/NEJMp0902248] [PMID: 19403901]
[11]
De Ferrari, G.M.; Dusi, V. Drug safety evaluation of dronedarone in atrial fibrillation. Expert Opin. Drug Saf., 2012, 11(6), 1023-1045.
[http://dx.doi.org/10.1517/14740338.2012.722994] [PMID: 22971242]
[12]
Santos, M.; García, L.C.; Checura, C.; Donadío, L.G.; Fernandez, C.; Orgueira, H.; Comin, M.J. Synthesis and characterization of new related substances of the antiarrhythmic drug dronedarone hydrochloride. J. Pharm. Biomed. Anal., 2015, 114, 441-446.
[http://dx.doi.org/10.1016/j.jpba.2015.06.026] [PMID: 26133102]
[13]
Oyetayo, O.O.; Rogers, C.E.; Hofmann, P.O. Dronedarone: A new antiarrhythmic agent. Pharmacotherapy, 2010, 30(9), 904-915.
[http://dx.doi.org/10.1592/phco.30.9.904] [PMID: 20795846]
[14]
McNamara, R.L.; Tamariz, L.J.; Segal, J.B.; Bass, E.B. Management of atrial fibrillation: Review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann. Intern. Med., 2003, 139(12), 1018-1033.
[http://dx.doi.org/10.7326/0003-4819-139-12-200312160-00012] [PMID: 14678922]
[15]
Singh, B.N.; Connolly, S.J.; Crijns, H.J.; Roy, D.; Kowey, P.R.; Capucci, A.; Radzik, D.; Aliot, E.M.; Hohnloser, S.H. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N. Engl. J. Med., 2007, 357(10), 987-999.
[http://dx.doi.org/10.1056/NEJMoa054686] [PMID: 17804843]
[16]
Patel, P.D.; Bhuriya, R.; Patel, D.D.; Arora, B.L.; Singh, P.P.; Arora, R.R. Dronedarone for atrial fibrillation: A new therapeutic agent. Vasc. Health Risk Manag., 2009, 5, 635-642.
[http://dx.doi.org/10.2147/VHRM.S6185]
[17]
Hu, G.X.; Dai, D.P.; Wang, H.; Huang, X.X.; Zhou, X.Y.; Cai, J.; Chen, H.; Cai, J.P. Systematic screening for CYP3A4 genetic polymorphisms in a Han Chinese population. Pharmacogenomics, 2017, 18(4), 369-379.
[http://dx.doi.org/10.2217/pgs-2016-0179] [PMID: 28244811]
[18]
Hong, Y.; Chia, Y.M.; Yeo, R.H.; Venkatesan, G.; Koh, S.K.; Chai, C.L.; Zhou, L.; Kojodjojo, P.; Chan, E.C. Inactivation of human cyto-chrome P450 3A4 and 3A5 by dronedarone and N-desbutyl dronedarone. Mol. Pharmacol., 2016, 89(1), 1-13.
[http://dx.doi.org/10.1124/mol.115.100891] [PMID: 26490246]
[19]
Zhou, X.Y.; Hu, X.X.; Wang, C.C.; Lu, X.R.; Chen, Z.; Liu, Q.; Hu, G.X.; Cai, J.P. Enzymatic activities of CYP3A4 allelic variants on quinine 3-hydroxylation in vitro. Front. Pharmacol., 2019, 10, 591.
[20]
Maekawa, K.; Harakawa, N.; Yoshimura, T.; Kim, S.R.; Fujimura, Y.; Aohara, F.; Sai, K.; Katori, N.; Tohkin, M.; Naito, M.; Hasegawa, R.; Okuda, H.; Sawada, J.; Niwa, T.; Saito, Y. CYP3A4*16 and CYP3A4*18 alleles found in East Asians exhibit differential catalytic activities for seven CYP3A4 substrate drugs. Drug Metab. Dispos., 2010, 38(12), 2100-2104.
[http://dx.doi.org/10.1124/dmd.110.034140] [PMID: 20847137]
[21]
Maekawa, K.; Yoshimura, T.; Saito, Y.; Fujimura, Y.; Aohara, F.; Emoto, C.; Iwasaki, K.; Hanioka, N.; Narimatsu, S.; Niwa, T.; Sawada, J. Functional characterization of CYP3A4.16: Catalytic activities toward midazolam and carbamazepine. Xenobiotica, 2009, 39(2), 140-147.
[http://dx.doi.org/10.1080/00498250802617746] [PMID: 19255940]
[22]
Westlind-Johnsson, A.; Hermann, R.; Huennemeyer, A.; Hauns, B.; Lahu, G.; Nassr, N.; Zech, K.; Ingelman-Sundberg, M.; von Richter, O. Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity. Clin. Pharmacol. Ther., 2006, 79(4), 339-349.
[http://dx.doi.org/10.1016/j.clpt.2005.11.015] [PMID: 16580902]
[23]
Murayama, N.; Nakamura, T.; Saeki, M.; Soyama, A.; Saito, Y.; Sai, K.; Ishida, S.; Nakajima, O.; Itoda, M.; Ohno, Y.; Ozawa, S.; Sawada, J. CYP3A4 gene polymorphisms influence testosterone 6 beta-hydroxylation. Drug Metab. Pharmacokinet., 2002, 17(2), 150-156.
[http://dx.doi.org/10.2133/dmpk.17.150] [PMID: 15618664]
[24]
Gonzalez, F.J.; Schmid, B.J.; Umeno, M.; Mcbride, O.W.; Hardwick, J.P.; Meyer, U.A.; Gelboin, H.V.; Idle, J.R. Human P450PCN1: Se-quence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase. DNA, 1988, 7(2), 79-86.
[http://dx.doi.org/10.1089/dna.1988.7.79] [PMID: 3267210]
[25]
Sata, F.; Sapone, A.; Elizondo, G.; Stocker, P.; Miller, V.P.; Zheng, W.; Raunio, H.; Crespi, C.L.; Gonzalez, F.J. CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: Evidence for an allelic variant with altered catalytic activity. Clin. Pharmacol. Ther., 2000, 67(1), 48-56.
[http://dx.doi.org/10.1067/mcp.2000.104391] [PMID: 10668853]
[26]
Miyazaki, M.; Nakamura, K.; Fujita, Y.; Guengerich, F.P.; Horiuchi, R.; Yamamoto, K. Defective activity of recombinant cytochromes P450 3A4.2 and 3A4.16 in oxidation of midazolam, nifedipine, and testosterone. Drug Metab. Dispos., 2008, 36(11), 2287-2291.
[http://dx.doi.org/10.1124/dmd.108.021816] [PMID: 18669585]
[27]
Fang, P.; Tang, P.F.; Xu, R.A.; Zheng, X.; Wen, J.; Bao, S.S.; Cai, J.P.; Hu, G.X. Functional assessment of CYP3A4 allelic variants on lido-caine metabolism in vitro. Drug Des. Devel. Ther., 2017, 11, 3503-3510.
[http://dx.doi.org/10.2147/DDDT.S152366]
[28]
Xu, R.A.; Wen, J.; Tang, P.; Wang, C.; Xie, S.; Zhang, B.W.; Zhou, Q.; Cai, J.P.; Hu, G.X. Functional characterization of 22 CYP3A4 protein variants to metabolize ibrutinib in vitro. Basic Clin. Pharmacol. Toxicol., 2018, 122(4), 383-387.
[http://dx.doi.org/10.1111/bcpt.12934] [PMID: 29117640]
[29]
Kumondai, M.; Gutiérrez Rico, E.M.; Hishinuma, E.; Ueda, A.; Saito, S.; Saigusa, D.; Tadaka, S.; Kinoshita, K.; Nakayoshi, T.; Oda, A.; Abe, A.; Maekawa, M.; Mano, N.; Hirasawa, N.; Hiratsuka, M. Functional characterization of 40 CYP3A4 variants by assessing midazolam 1′-hydroxylation and testosterone 6β-hydroxylation. Drug Metab. Dispos., 2021, 49(3), 212-220.
[http://dx.doi.org/10.1124/dmd.120.000261] [PMID: 33384383]
[30]
Dai, D.; Tang, J.; Rose, R.; Hodgson, E.; Bienstock, R.J.; Mohrenweiser, H.W.; Goldstein, J.A. Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J. Pharmacol. Exp. Ther., 2001, 299(3), 825-831.
[PMID: 11714865]
[31]
Hsieh, K.P.; Lin, Y.Y.; Cheng, C.L.; Lai, M.L.; Lin, M.S.; Siest, J.P.; Huang, J.D. Novel mutations of CYP3A4 in Chinese. Drug Metab. Dispos., 2001, 29(3), 268-273.
[PMID: 11181494]
[32]
Pratt-Hyatt, M.; Zhang, H.; Snider, N.T.; Hollenberg, P.F. Effects of a commonly occurring genetic polymorphism of human CYP3A4 (I118V) on the metabolism of anandamide. Drug Metab. Dispos., 2010, 38(11), 2075-2082.
[33]
Yang, C.C.; Zheng, X.; Liu, T.H.; Wang, C.C.; Tang, P.F.; Chen, Z.; Zhang, B.W.; Fang, P.; Hu, G.X.; Cai, J.P. Functional characterization of 21 CYP3A4 variants on amiodarone metabolism in vitro. Xenobiotica, 2019, 49(1), 120-126.
[http://dx.doi.org/10.1080/00498254.2017.1414971] [PMID: 29394111]
[34]
Nakajima, Y.; Yoshitani, T.; Fukushima-Uesaka, H.; Saito, Y.; Kaniwa, N.; Kurose, K.; Ozawa, S.; Aoyagi, N.; Kamatani, N.; Yamamoto, N.; Kunitoh, H.; Ohe, Y.; Tamura, T.; Yoshida, T.; Minami, H.; Saijo, N.; Katori, N.; Sawada, J. Impact of the haplotype CYP3A4*16B harboring the Thr185Ser substitution on paclitaxel metabolism in Japanese patients with cancer. Clin. Pharmacol. Ther., 2006, 80(2), 179-191.
[http://dx.doi.org/10.1016/j.clpt.2006.04.012] [PMID: 16890579]
[35]
Lee, S.J.; Bell, D.A.; Coulter, S.J.; Ghanayem, B.; Goldstein, J.A. Recombinant CYP3A4*17 is defective in metabolizing the hypertensive drug nifedipine, and the CYP3A4*17 allele may occur on the same chromosome as CYP3A5*3, representing a new putative defective CYP3A haplotype. J. Pharmacol. Exp. Ther., 2005, 313(1), 302-309.
[http://dx.doi.org/10.1124/jpet.104.078758] [PMID: 15634941]
[36]
Kang, Y.S.; Park, S.Y.; Yim, C.H.; Kwak, H.S.; Gajendrarao, P.; Krishnamoorthy, N.; Yun, S.C.; Lee, K.W.; Han, K.O. The CYP3A4*18 gen-otype in the cytochrome P450 3A4 gene, a rapid metabolizer of sex steroids, is associated with low bone mineral density. Clin. Pharmacol. Ther., 2009, 85(3), 312-318.
[http://dx.doi.org/10.1038/clpt.2008.215] [PMID: 19020497]
[37]
Kumar, P.; Henikoff, S.; Ng, P.C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc., 2009, 4(7), 1073-1081.
[http://dx.doi.org/10.1038/nprot.2009.86] [PMID: 19561590]
[38]
Adzhubei, I.A.; Schmidt, S.; Peshkin, L.; Ramensky, V.E.; Gerasimova, A.; Bork, P.; Kondrashov, A.S.; Sunyaev, SR A method and server for predicting damaging missense mutations. Nat. Methods, 2010, 7(4), 248-249.
[http://dx.doi.org/10.1038/nmeth0410-248]
[39]
Ozdemir, V.; Kalow, W.; Tang, B.K.; Paterson, A.D.; Walker, S.E.; Endrenyi, L.; Kashuba, A.D. Evaluation of the genetic component of vari-ability in CYP3A4 activity: A repeated drug administration method. Pharmacogenetics, 2000, 10(5), 373-388.
[http://dx.doi.org/10.1097/00008571-200007000-00001] [PMID: 10898107]

Rights & Permissions Print Cite
Article Metrics
9
© 2024 Bentham Science Publishers | Privacy Policy