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

The Effect of Retroconversion Metabolism of N-oxide Metabolites by Intestinal Microflora on Piperaquine Elimination in Mice, as well as in Humans Predicted Using a PBPK Model

Author(s): Hongchang Zhou, Liyuan Zhang, Jianbo Ji, Yuewu Xie and Jie Xing*

Volume 24, Issue 2, 2023

Published on: 07 April, 2023

Page: [131 - 138] Pages: 8

DOI: 10.2174/1389200224666230320112429

Price: $65

Abstract

Background: Piperaquine (PQ) and its pharmacologically active metabolite PQ N-oxide (PM1) can be metabolically interconverted via hepatic cytochrome P450 and FMO enzymes.

Objectives: The reductive metabolism of PM1 and its further N-oxidation metabolite (PM2) by intestinal microflora was evaluated, and its role in PQ elimination was also investigated.

Methods: The hepatic and microbial reduction metabolism of PM1 and PM2 was studied in vitro. The reaction phenotyping experiments were performed using correlation analysis, selective chemical inhibition, and human recombinant CYP/FMO enzymes. The role of microbial reduction metabolism in PQ elimination was evaluated in mice pretreated with antibiotics. The effect of the reduction metabolism on PQ exposures in humans was predicted using a physiologically-based pharmacokinetic (PBPK) model.

Results: Both hepatic P450/FMOs enzymes and microbial nitroreductases (NTRs) contributed to the reduction metabolism of two PQ N-oxide metabolites. In vitro physiologic and enzyme kinetic studies of both N-oxides showed a comparable intrinsic clearance by the liver and intestinal microflora. Pretreatment with antibiotics did not lead to a significant (P > 0.05) change in PQ pharmacokinetics in mice after an oral dose. The predicted pharmacokinetic profiles of PQ in humans did not show an effect of metabolic recycling.

Conclusion: Microbial NTRs and hepatic P450/FMO enzymes contributed to the reduction metabolism of PQ Noxide metabolites. The reduction metabolism by intestinal microflora did not affect PQ clearance, and the medical warning in patients with NTRs-related disease (e.g., hyperlipidemia) will not be clinically meaningful.

« Previous Next »
Graphical Abstract

[1]
Guidelines for the Treatment of Malaria, 3rd ed; WHO: Geneva, Switzerland, 2015.
[2]
Hanboonkunupakarn, B.; White, N.J. Advances and roadblocks in the treatment of malaria. Br. J. Clin. Pharmacol., 2022, 88(2), 374-382.
[http://dx.doi.org/10.1111/bcp.14474] [PMID: 32656850]
[3]
Erhunse, N.; Sahal, D. Protecting future antimalarials from the trap of resistance: Lessons from artemisinin-based combination therapy (ACT) failures. J. Pharm. Anal., 2021, 11(5), 541-554.
[http://dx.doi.org/10.1016/j.jpha.2020.07.005] [PMID: 34765267]
[4]
Chotsiri, P.; Gutman, J.R.; Ahmed, R.; Poespoprodjo, J.R.; Syafruddin, D.; Khairallah, C.; Asih, P.B.S.; L’lanziva, A.; Otieno, K.; Kariuki, S.; Ouma, P.; Were, V.; Katana, A.; Price, R.N.; Desai, M.; ter Kuile, F.O.; Tarning, J. Piperaquine pharmacokinetics during intermittent preventive treatment for malaria in pregnancy. Antimicrob. Agents Chemother., 2021, 65(3), e01150-e01152.
[http://dx.doi.org/10.1128/AAC.01150-20] [PMID: 33361303]
[5]
Wallender, E.; Ali, A.M.; Hughes, E.; Kakuru, A.; Jagannathan, P.; Muhindo, M.K.; Opira, B.; Whalen, M.; Huang, L.; Duvalsaint, M.; Legac, J.; Kamya, M.R.; Dorsey, G.; Aweeka, F.; Rosenthal, P.J.; Savic, R.M. Identifying an optimal dihydroartemisinin-piperaquine dosing regimen for malaria prevention in young Ugandan children. Nat. Commun., 2021, 12(1), 6714.
[http://dx.doi.org/10.1038/s41467-021-27051-8] [PMID: 34795281]
[6]
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]
[7]
Lee, T.M.N.; 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]
[8]
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), e00260-18.
[http://dx.doi.org/10.1128/AAC.00260-18] [PMID: 29784841]
[9]
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]
[10]
Hirosawa, K.; Fukami, T.; Nagaoka, M.; Nakano, M.; Nakajima, M. Methionine sulfoxide reductase A in human and mouse tissues is responsible for sulindac activation, making a larger contribution than the gut microbiota. Drug Metab. Dispos., 2022, 50(5), 725-733.
[http://dx.doi.org/10.1124/dmd.122.000828] [PMID: 35279645]
[11]
Ebuzoeme, C.; Etim, I.; Ikimi, A.; Song, J.; Du, T.; Hu, M.; Liang, D.; Gao, S. Glucuronides hydrolysis by intestinal microbial β-glucuronidases (GUS) is affected by sampling, enzyme preparation, buffer pH, and species. Pharmaceutics, 2021, 13(7), 1043.
[http://dx.doi.org/10.3390/pharmaceutics13071043] [PMID: 34371734]
[12]
Garcia, W.L.; Miller, C.J.; Lomas, G.X.; Gaither, K.A.; Tyrrell, K.J.; Smith, J.N.; Brandvold, K.R.; Wright, A.T. Profiling how the gut microbiome modulates host xenobiotic metabolism in response to benzo[a]pyrene and 1-nitropyrene exposure. Chem. Res. Toxicol., 2022, 35(4), 585-596.
[http://dx.doi.org/10.1021/acs.chemrestox.1c00360] [PMID: 35347982]
[13]
Tirelle, P.; Breton, J.; Riou, G.; Déchelotte, P.; Coëffier, M.; Ribet, D. Comparison of different modes of antibiotic delivery on gut microbiota depletion efficiency and body composition in mouse. BMC Microbiol., 2020, 20(1), 340.
[http://dx.doi.org/10.1186/s12866-020-02018-9] [PMID: 33176677]
[14]
F, R.; G, H.; P, L. Purification and characterization of an enzyme from Mycobacterium sp. Pyr-1, with nitroreductase activity and an N-terminal sequence similar to lipoamide dehydrogenase. Arch. Microbiol., 2001, 176(5), 381-385.
[http://dx.doi.org/10.1007/s002030100337] [PMID: 11702081]
[15]
Tarning, J.; Lindegardh, N. Quantification of the antimalarial piperaquine in plasma. Trans. R. Soc. Trop. Med. Hyg., 2008, 102(5), 409-411.
[http://dx.doi.org/10.1016/j.trstmh.2008.02.011] [PMID: 18378269]
[16]
Taneja, I.; Raju, K.S.R.; Singh, S.P.; Wahajuddin, M. Assessment of pharmacokinetic compatibility of short acting CDRI candidate trioxane derivative, 99–411, with long acting prescription antimalarials, lumefantrine and piperaquine. Sci. Rep., 2015, 5(1), 17264.
[http://dx.doi.org/10.1038/srep17264] [PMID: 26602250]
[17]
Huang, J. Studies on pharmacokinetics and bioequivalence of dihydroartemisinin and piperaquine phosphate tablets with parallel design. Master's Thesis, Shandong University: 2013.
[18]
Tarning, J.; Lindegardh, N.; Sandberg, S.; Day, N.J.P.; White, N.J.; Ashton, M. Pharmacokinetics and metabolism of the antimalarial piperaquine after intravenous and oral single doses to the rat. J. Pharm. Sci., 2008, 97(8), 3400-3410.
[http://dx.doi.org/10.1002/jps.21226] [PMID: 17969131]
[19]
Guo, Y.; Lee, H.; Jeong, H. Gut microbiota in reductive drug metabolism. Prog. Mol. Biol. Transl. Sci., 2020, 171, 61-93.
[http://dx.doi.org/10.1016/bs.pmbts.2020.04.002] [PMID: 32475528]
[20]
Hertli, S.; Zimmermann, P. Molecular interactions between the intestinal microbiota and the host. Mol. Microbiol., 2022, 117(6), 1297-1307.
[http://dx.doi.org/10.1111/mmi.14905] [PMID: 35403275]
[21]
Boddu, R.S.; Perumal, O. K, D. Microbial nitroreductases: A versatile tool for biomedical and environmental applications. Biotechnol. Appl. Biochem., 2021, 68(6), 1518-1530.
[PMID: 33156534]
[22]
DʼAlessandro, U. Progress in the development of piperaquine combinations for the treatment of malaria. Curr. Opin. Infect. Dis., 2009, 22(6), 588-592.
[http://dx.doi.org/10.1097/QCO.0b013e328332674a] [PMID: 19773652]

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