Effects of MAO-A and CYP450 on primaquine metabolism in healthy volunteers
Eliminating the Plasmodium vivax malaria parasite infection remains challenging. One of the main problems is its capacity to form hypnozoites that potentially lead to recurrent infections. At present, primaquine is the only drug used for the management of hypnozoites. However, the effects of primaquine may differ from one individual to another. The aim of this work is to determine new measures to reduce P. vivax recurrence, through primaquine metabolism and host genetics. A genetic study of MAO-A, CYP2D6, CYP1A2 and CYP2C19 and their roles in primaquine metabolism was undertaken of healthy volunteers (n = 53). The elimination rate constant (Ke) and the metabolite-to-parent drug concentration ratio (Cm/Cp) were obtained to assess primaquine metabolism. Allelic and genotypic analysis showed that polymorphisms MAO-A (rs6323, 891G>T), CYP2D6 (rs1065852, 100C>T) and CYP2C19 (rs4244285, 19154G>A) significantly influenced primaquine metabolism. CYP1A2 (rs762551, -163C>A) did not influence primaquine metabolism. In haplotypic analysis, significant differences in Ke (p = 0.00) and Cm/Cp (p = 0.05) were observed between individuals with polymorphisms, GG-MAO-A (891G>T), CT-CYP2D6 (100C>T) and GG-CYP2C19 (19154G>A), and individuals with polymorphisms, TT-MAO-A (891G>T), TT-CYP2D6 (100C>T) and AA-CYP2C19 (19154G>A), as well as polymorphisms, GG-MAO-A (891G>T), TT-CYP2D6 (100C>T) and GA-CYP2C19 (19154G>A). Thus, individuals with CYP2D6 polymorphisms had slower primaquine metabolism activity. The potential significance of genetic roles in primaquine metabolism and exploration of these might help to further optimise the management of P. vivax infection.
KeywordsPlasmodium vivax Malaria Polymorphism Primaquine
This study was funded by the Ministry of Higher Education, Malaysia, under the Fundamental Research Grant Scheme [FRGS/1/2016/SKK09/UKM/02/1].
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- Constantino L, Paixao P, Moreira R, Portela MJ, Do Rosario VE, Iley J (1999) Metabolism of primaquine by liver homogenate fractions: evidence for monoamine oxidase and cytochrome P450 involvement in the oxidative deamination of primaquine to carboxyprimaquine. Exp Toxicol Pathol 51(4–5):299–303CrossRefGoogle Scholar
- European Medicines Agency (2011) Guideline on plasma-derived medicinal products. EMA/CHMP/BWP/706271/2010, 21 July 2011Google Scholar
- Jin X, Pybus BS, Marcsisin SR, Logan T, Luong TL, Sousa J, Matlock N, Collazo V, Asher C, Carroll D, Olmeda R (2014) An LC–MS based study of the metabolic profile of primaquine, an 8-aminoquinoline antiparasitic drug, with an in vitro primary human hepatocyte culture model. Eur J Drug Metab Pharmacokinet 39(2):139–146CrossRefGoogle Scholar
- Li T, Sheng J, Li W, Zhang X, Yu H, Chen X, Zhang J, Cai Q, Shi Y, Liu Z (2015) A new computational model for human thyroid cancer enhances the preoperative diagnostic efficacy. Oncotarget 6(29):28463–28477Google Scholar
- Makmor Bakry M (2007) Influence of genetic variability on the clinical pharmacology of carbamazepine and lamotrigine (Doctoral dissertation, University of Glasgow)Google Scholar
- Murray CJ, Ortblad KF, Guinovart C, Lim SS, Wolock TM, Roberts DA, Dansereau EA, Graetz N, Barber RM, Brown JC, Wang H (2013) Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the global burden of disease study 2013. Lancet 384(9947):1005–1070CrossRefGoogle Scholar
- Nimir AR, Isa NH, Chan BT, Ghauth IM, Salleh FM, Rahman RA (2006) Severity of malaria cases reported in urban and rural hospitals in Malaysia. Southeast Asian J Trop Med Public Health 37(5):831–837Google Scholar
- Noryahati M, Rohani AK, Hayati MN, Halimah AS, Sharom MY, Abidin AZ, Fatimah MS (2001) Clinical features of malaria in orang Asli population in Pos Piah, Malaysia. Med J Malaysia 56(3):271–274Google Scholar
- Radhakrishnan AK, Raj VL, Tan LK, Liam CK (2013) Single nucleotide polymorphism in the promoter of the human interleukin-13 gene is associated with asthma in Malaysian adults. Biomed Res Int:1–7Google Scholar
- Roederer MW, McLeod H, Juliano JJ (2011) Can pharmacogenomics improve malaria drug policy? Bull WHO 89:838–845Google Scholar
- Sen A (2016) CYP2D6: a global analysis of phenotypic and genotypic variation in search of radical cure of Plasmodium vivax malaria (Doctoral dissertation)Google Scholar
- Tekwani BL, Avula B, Sahu R, Chaurasiya ND, Khan SI, Jain S, Fasinu PS, Herath HB, Stanford D, Nanayakkara ND, McChesney JD (2015) Enantioselective pharmacokinetics of primaquine in healthy human volunteers. Drug Metab Dispos 30:dmd–114Google Scholar
- World Health Organization (2015) World malaria report 2014. World Health Organization, 2015 Jul 7Google Scholar
- World Medical Association (2013) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310(20):2191Google Scholar
- Yu CY, Ang GY, Subramaniam V, Johari James R, Ahmad A, Abdul Rahman T, Mohd Nor F, Shaari SA, Teh LK, Salleh MZ (2017) Inference of the genetic polymorphisms of CYP2D6 in six subtribes of the malaysian orang asli from whole-genome sequencing data. Genet Test Mol Biomarkers 21(7):409–415CrossRefGoogle Scholar