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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

No Effect of PXR (8055C>T) Polymorphism on the Pharmacokinetic Profiles of Piperaquine in Healthy Chinese Subjects

Author(s): Huixiang Liu, Yuewu Xie, Tianyu Cai and Jie Xing*

Volume 23, Issue 2, 2022

Published on: 02 March, 2022

Page: [164 - 170] Pages: 7

DOI: 10.2174/1389200223666220215151945

Price: $65

Abstract

Background: Significant inter-subject variability in pharmacokinetics and clinical outcomes has been observed for the antimalarial agent piperaquine (PQ). PQ is metabolized by CYP3A4, mainly regulated by the pregnane X receptor (PXR). CYP3A4(*1B) polymorphism did not affect PQ clearance.

Objectives: The effect of PXR (8055C>T) polymorphism on the pharmacokinetic profiles of PQ was investigated.

Methods: The pharmacokinetic profiles of PQ and its major metabolite PQ N-oxide (PQM) were studied in healthy Chinese subjects after recommended oral doses of artemisinin-PQ. Twelve subjects were genotyped using PCRRFLP (six in each group with PXR 8055CC and 8055TT), and plasma concentrations were determined by a validated LC/MS/MS method. The dose-adjusted exposure (AUC and Cmax) to PQ or PQM was investigated, and the metabolic capability of PQ N-oxidation was determined by AUCPQM/AUCPQ. The antimalarial outcome of PQ was evaluated using its day 7 concentration.

Results: PQM formation was mediated by CYP3A4/3A5. Interindividual variability in dose-adjusted AUC of PQ and PQM was relatively low (%CV, <30.0%), whereas a larger inter-variability was observed for Cmax values (%CV, 68.1% for PQ). No polymorphic effect was found for PXR (C8055T) on the pharmacokinetic profiles of PQ or its Cday 7 concentrations.

Conclusion: Both CYP3A4 and CYP3A5 were involved in PQ clearance. The genotypes of PXR (C8055T) may not contribute to the variability in PQ pharmacokinetics as well as antimalarial outcomes. There might be a low risk of variable exposures to PQ in malaria patients carrying mutated PXR (8055C>T) genes, which deserves further study, especially in a larger sample size.

Keywords: Piperaquine, metabolite, PXR, polymorphism, pharmacokinetics, healthy adults.

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[1]
WHO. Guidelines for the Treatment of Malaria, 3rd ed; Geneva, Switzerland, 2015.
[2]
Woodrow, C.J.; White, N.J. The clinical impact of artemisinin resistance in Southeast Asia and the potential for future spread. FEMS Microbiol. Rev., 2017, 41(1), 34-48.
[http://dx.doi.org/10.1093/femsre/fuw037] [PMID: 27613271 ]
[3]
Hodoameda, P.; Duah-Quashie, N.O.; Hagan, C.O.; Matrevi, S.; Abuaku, B.; Koram, K.; Quashie, N.B. Plasmodium falciparum genetic factors rather than host factors are likely to drive resistance to ACT in Ghana. Malar. J., 2020, 19(1), 255.
[http://dx.doi.org/10.1186/s12936-020-03320-7] [PMID: 32669113 ]
[4]
Funck-Brentano, C.; Ouologuem, N.; Duparc, S.; Felices, M.; Sirima, S.B.; Sagara, I.; Soulama, I.; Ouedraogo, J.B.; Beavogui, A.H. Borghini- Fuhrer, I.; Khan, Y.; Djimdé, A.A.; Voiriot, P. Evaluation of the effects on the QT-interval of 4 artemisinin-based combination therapies with a correction-free and heart rate-free method. Sci. Rep., 2019, 9(1), 883.
[http://dx.doi.org/10.1038/s41598-018-37113-5] [PMID: 30696921 ]
[5]
Leang, R.; Taylor, W.R.; Bouth, D.M.; Song, L.; Tarning, J.; Char, M.C.; Kim, S.; Witkowski, B.; Duru, V.; Domergue, A.; Khim, N.; Ringwald, P.; Menard, D. Evidence of Plasmodium falciparum malaria multidrug resistance to artemisinin and piperaquine in Western Cambodia: Dihydroartemisinin-piperaquine open-label multicenter clinical assessment. Antimicrob. Agents Chemother., 2015, 59(8), 4719-4726.
[http://dx.doi.org/10.1128/AAC.00835-15] [PMID: 26014949 ]
[6]
Onyamboko, M.A.; Fanello, C.I.; Wongsaen, K.; Tarning, J.; Cheah, P.Y.; Tshefu, K.A.; Dondorp, A.M.; Nosten, F.; White, N.J.; Day, N.P. Randomized comparison of the efficacies and tolerabilities of three artemisinin- based combination treatments for children with acute Plasmodium falciparum malaria in the Democratic Republic of the Congo. Antimicrob. Agents Chemother., 2014, 58(9), 5528-5536.
[http://dx.doi.org/10.1128/AAC.02682-14] [PMID: 25001306 ]
[7]
Liu, H.; Zhou, H.; Cai, T.; Yang, A.; Zang, M.; Xing, J. Metabolism of piperaquine to its antiplasmodial metabolites and their pharmacokinetic profiles in healthy volunteers. Antimicrob. Agents Chemother., 2018, 62(8), e00260-e18.
[http://dx.doi.org/10.1128/AAC.00260-18] [PMID: 29784841 ]
[8]
Tarning, J.; Lindegardh, N.; Lwin, K.M.; Annerberg, A.; Kiricharoen, L.; Ashley, E.; White, N.J.; Nosten, F.; Day, N.P. Population pharmacokinetic assessment of the effect of food on piperaquine bioavailability in patients with uncomplicated malaria. Antimicrob. Agents Chemother., 2014, 58(4), 2052-2058.
[http://dx.doi.org/10.1128/AAC.02318-13] [PMID: 24449770 ]
[9]
Adam, I.; Tarning, J.; Lindegardh, N.; Mahgoub, H.; McGready, R.; Nosten, F. Pharmacokinetics of piperaquine in pregnant women in Sudan with uncomplicated Plasmodium falciparum malaria. Am. J. Trop. Med. Hyg., 2012, 87(1), 35-40.
[http://dx.doi.org/10.4269/ajtmh.2012.11-0410] [PMID: 22764289 ]
[10]
Karunajeewa, H.A.; Ilett, K.F.; Mueller, I.; Siba, P.; Law, I. Page- Sharp, M.; Lin, E.; Lammey, J.; Batty, K.T.; Davis, T.M. Pharmacokinetics and efficacy of piperaquine and chloroquine in Melanesian children with uncomplicated malaria. Antimicrob. Agents Chemother., 2008, 52(1), 237-243.
[http://dx.doi.org/10.1128/AAC.00555-07] [PMID: 17967917 ]
[11]
Keating, G.M. Dihydroartemisinin/Piperaquine: A review of its use in the treatment of uncomplicated Plasmodium falciparum malaria. Drugs, 2012, 72(7), 937-961.
[http://dx.doi.org/10.2165/11203910-000000000-00000] [PMID: 22515619 ]
[12]
Xie, Y.; Zhang, Y.; Liu, H.; Xing, J. Metabolic retroversion of piperaquine (PQ) via hepatic cytochrome P450-mediated N-oxidation and reduction: Not an important contributor to the prolonged elimination of PQ. Drug Metab. Dispos., 2021, 49(5), 379-388.
[http://dx.doi.org/10.1124/dmd.120.000306] [PMID: 33674271 ]
[13]
Tarning, J.; Bergqvist, Y.; Day, N.P.; Bergquist, J.; Arvidsson, B.; White, N.J.; Ashton, M.; Lindegårdh, N. Characterization of human urinary metabolites of the antimalarial piperaquine. Drug Metab. Dispos., 2006, 34(12), 2011-2019.
[http://dx.doi.org/10.1124/dmd.106.011494] [PMID: 16956956 ]
[14]
Staehli Hodel, E.M.; Guidi, M.; Zanolari, B.; Mercier, T.; Duong, S.; Kabanywanyi, A.M.; Ariey, F.; Buclin, T.; Beck, H.P.; Decosterd, L.A.; Olliaro, P.; Genton, B.; Csajka, C. Population pharmacokinetics of mefloquine, piperaquine and artemether-lumefantrine in Cambodian and Tanzanian malaria patients. Malar. J., 2013, 12(1), 235.
[http://dx.doi.org/10.1186/1475-2875-12-235] [PMID: 23841950 ]
[15]
Sundell, K.; Jagannathan, P.; Huang, L.; Bigira, V.; Kapisi, J.; Kakuru, M.M.; Savic, R.; Kamya, M.R.; Dorsey, G.; Aweeka, F. Variable piperaquine exposure significantly impacts protective efficacy of monthly dihydroartemisinin-piperaquine for the prevention of malaria in Ugandan children. Malar. J., 2015, 14(1), 368.
[http://dx.doi.org/10.1186/s12936-015-0908-8] [PMID: 26403465 ]
[16]
Zhang, L.; Liu, Z.; Zhang, Y.; Xie, Y.; Xing, J. Metabolism is not a major contributor to the toxicity of piperaquine, a long-acting antimalarial agent in artemisinin-based combination therapy. Curr. Drug Metab., 2021, 22(10), 824-834.
[http://dx.doi.org/10.2174/1389200222666210928124943] [PMID: 34602032 ]
[17]
Lee, T.M.; Huang, L.; Johnson, M.K.; Lizak, P.; Kroetz, D.; Aweeka, F.; Parikh, S. In vitro metabolism of piperaquine is primarily mediated by CYP3A4. Xenobiotica, 2012, 42(11), 1088-1095.
[http://dx.doi.org/10.3109/00498254.2012.693972] [PMID: 22671777 ]
[18]
Wang, C.E.; Lu, K.P.; Chang, Z.; Guo, M.L.; Qiao, H.L. Association of CYP3A4*1B genotype with Cyclosporin A pharmacokinetics in renal transplant recipients: A meta-analysis. Gene, 2018, 664, 44-49.
[http://dx.doi.org/10.1016/j.gene.2018.04.043] [PMID: 29678659 ]
[19]
Elens, L.; Nieuweboer, A.; Clarke, S.J.; Charles, K.A.; de Graan, A.J.; Haufroid, V.; Mathijssen, R.H.; van Schaik, R.H. CYP3A4 intron 6 C>T SNP (CYP3A4*22) encodes lower CYP3A4 activity in cancer patients, as measured with probes midazolam and erythromycin. Pharmacogenomics, 2013, 14(2), 137-149.
[http://dx.doi.org/10.2217/pgs.12.202] [PMID: 23327575 ]
[20]
Liu, J.; Chen, Z.; Chen, H.; Hou, Y.; Lu, W.; He, J.; Tong, H.; Zhou, Y.; Cai, W. Genetic polymorphisms contribute to the individual variations of imatinib mesylate plasma levels and adverse reactions in Chinese GIST patients. Int. J. Mol. Sci., 2017, 18(3), 603.
[http://dx.doi.org/10.3390/ijms18030603] [PMID: 28335376 ]
[21]
Collins, J.M.; Wang, D. Regulation of CYP3A4 and CYP3A5 by a lncRNA: A potential underlying mechanism explaining the association between CYP3A4*1G and CYP3A metabolism. Pharmacogenet. Genomics, 2022, 32(1), 16-23.
[http://dx.doi.org/10.1097/FPC.0000000000000447] [PMID: 34320606 ]
[22]
Lamba, J.K.; Lin, Y.S.; Schuetz, E.G.; Thummel, K.E. Genetic contribution to variable human CYP3A-mediated metabolism. Adv. Drug Deliv. Rev., 2002, 54(10), 1271-1294.
[http://dx.doi.org/10.1016/S0169-409X(02)00066-2] [PMID: 12406645 ]
[23]
Mutagonda, R.F.; Minzi, O.M.S.; Massawe, S.N.; Asghar, M.; Färnert, A.; Kamuhabwa, A.A.R.; Aklillu, E. Pregnancy and CYP3A5 genotype affect day 7 plasma lumefantrine concentrations. Drug Metab. Dispos., 2019, 47(12), 1415-1424.
[http://dx.doi.org/10.1124/dmd.119.088062] [PMID: 31744845 ]
[24]
Staehli Hodel, E.M.; Csajka, C.; Ariey, F.; Guidi, M.; Kabanywanyi, A.M.; Duong, S.; Decosterd, L.A.; Olliaro, P.; Beck, H.P.; Genton, B. Effect of single nucleotide polymorphisms in cytochrome P450 isoenzyme and N-acetyltransferase 2 genes on the metabolism of artemisinin- based combination therapies in malaria patients from Cambodia and Tanzania. Antimicrob. Agents Chemother., 2013, 57(2), 950-958.
[http://dx.doi.org/10.1128/AAC.01700-12] [PMID: 23229480 ]
[25]
Kong, F.C.; Ma, C.L.; Lang, L.Q.; Zhong, M.K. Association of xenobiotic receptor polymorphisms with carbamazepine response in epilepsy patients. Gene, 2021, 771, 145359.
[http://dx.doi.org/10.1016/j.gene.2020.145359] [PMID: 33333223]
[26]
Lu, T.; Zhu, X.; Xu, S.; Zhao, M.; Huang, X.; Wang, Z.; Zhao, L. Dosage optimization based on population pharmacokinetic analysis of tacrolimus in Chinese patients with nephrotic syndrome. Pharm. Res., 2019, 36(3), 45.
[http://dx.doi.org/10.1007/s11095-019-2579-6] [PMID: 30719576 ]
[27]
Quang, N.N.; Chavchich, M.; Anh, C.X.; Birrell, G.W.; van Breda, K.; Travers, T.; Rowcliffe, K.; Edstein, M.D. Comparison of the pharmacokinetics and ex vivo antimalarial activities of artesunateamodiaquine and artemisinin-piperaquine in healthy volunteers for preselection malaria therapy., Am. J. Trop. Med. Hyg., 2018, 99(1), 65-72.
[http://dx.doi.org/10.4269/ajtmh.17-0434 ] [PMID: 29741150]

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