The online version of this article (doi:10.1186/1475-2875-11-259) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
BSP and JCS: manuscript preparation, experimental design, data analysis and interpretation; JF, REC and CV: mass spectrometry; RB: enzyme kinetics; RJS and GAR: data interpretation, figure preparation; XJ: experimental design, data analysis and interpretation; MPK: funding, experimental design, manuscript preparation; LAW, CO and VM: funding, experimental design. Each author read and approved the final version of this manuscript.
The 8-aminoquinoline (8AQ) drug primaquine (PQ) is currently the only approved drug effective against the persistent liver stage of the hypnozoite forming strains Plasmodium vivax and Plasmodium ovale as well as Stage V gametocytes of Plasmodium falciparum. To date, several groups have investigated the toxicity observed in the 8AQ class, however, exact mechanisms and/or metabolic species responsible for PQ’s haemotoxic and anti-malarial properties are not fully understood.
In the present study, the metabolism of PQ was evaluated using in vitro recombinant metabolic enzymes from the cytochrome P450 (CYP) and mono-amine oxidase (MAO) families. Based on this information, metabolite identification experiments were performed using nominal and accurate mass measurements.
Relative activity factor (RAF)-weighted intrinsic clearance values show the relative role of each enzyme to be MAO-A, 2C19, 3A4, and 2D6, with 76.1, 17.0, 5.2, and 1.7% contributions to PQ metabolism, respectively. CYP 2D6 was shown to produce at least six different oxidative metabolites along with demethylations, while MAO-A products derived from the PQ aldehyde, a pre-cursor to carboxy PQ. CYPs 2C19 and 3A4 produced only trace levels of hydroxylated species.
As a result of this work, CYP 2D6 and MAO-A have been implicated as the key enzymes associated with PQ metabolism, and metabolites previously identified as potentially playing a role in efficacy and haemolytic toxicity have been attributed to production via CYP 2D6 mediated pathways.
WHO: World Malaria Report 2011. 2011, World Health Organization, Geneva
Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM: Vivax malaria: neglected and not benign. AmJTrop Med Hyg. 2007, 77: 79-87.
Bolchoz LJ, Budinsky RA, McMillan DC, Jollow DJ: Primaquine-induced hemolytic anemia: formation and hemotoxicity of the arylhydroxylamine metabolite 6-methoxy-8-hydroxylaminoquinoline. J Pharmacol Exp Ther. 2001, 297: 509-515. PubMed
Vasquez-Vivar J, Augusto O: Hydroxylated metabolites of the antimalarial drug primaquine. JBC. 1992, 267: 6848-6854.
Beutler E: Drug-induced hemolytic anemia. Pharmacol Rev. 1969, 21: 73-103. PubMed
Ganesan S, Tekwani BL, Sahu R, Tripathi LM, Walker LA: Cytochrome P450-dependent toxic effects of primaquine on human erythrocytes. Tox App Pharm. 2009, 241: 14-22. 10.1016/j.taap.2009.07.012. CrossRef
Constantino L, Paixao P, Moreira R, Portela MJ, Do Rosario VE, Iley J: Metabolism of primaquine by liver homogenate fractions: Evidence for monoamine oxidase and cytochrome P450 involvement in the oxidative deamination of primaquine to carboxyprimaquine. Exp Toxic Pathol. 1999, 51: 299-303. 10.1016/S0940-2993(99)80010-4. CrossRef
Brossi A, Millet P, Landau I, Bembenek ME, Abell CW: Antimalarial activity and inhibition of monoamine oxidases A and B by exo-erythrocytic antimalarials. FEBS. 1987, 214: 291-294. 10.1016/0014-5793(87)80072-8. CrossRef
Gia PT, deVries PJ: Pharmacokinetic interactions of antimalarial agents. Clin Pharmacokinet. 2001, 40: 343-373. 10.2165/00003088-200140050-00003. CrossRef
Idowu OR, Peggins JO, Brewer TG: Side-chain hydroxylation in the metabolism of 8-aminoquinoline antiparasitic agents. Drug Metab Dispos. 1995, 23: 18-27. PubMed
Neafsey P, Ginsberg G, Hattis D, Sonawane B: Genetic polymorphism in cytochrome P450 2D6 (CYP2D6): population distribution of CYP2D6 activity. J Tox Env Health B. 2009, 12: 334-361. 10.1080/10937400903158342. CrossRef
- CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine
Brandon S Pybus
Jason C Sousa
James A Ferguson
Robert E Christian
Richard J Sciotti
Gregory A Reichard
Michael P Kozar
Larry A Walker
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
e.Med Kampagnen-Visual, Mail Icon II