Volume 85, Issue 6
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Because 8-aminoquinolines affect critical survival stages of parasites, treatment and control of malaria could be markedly improved by more widespread use of these drugs; however, hemolytic toxicity, which is widely prevalent in G6PD-deficient patients, severely constrains this use. Primaquine was approved more than 50 years ago after extensive clinical testing. Review of the mid-20th century literature in the light of present understanding of pharmacokinetics and metabolism suggests that manipulation of these factors might dissociate 8-aminoquinoline efficacy from toxicity and lead to an improved therapeutic index.


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  1. Baird JK, Fryauff DJ, Basri H, Bangs MJ, Subianto B, Wiady I, Purnomo, Leksana B, Masbar S, Richie TL, Jones TR, Tjitra E, Wignall ES, Hoffman SL, , 1995. Primaquine for prophylaxis against malaria among nonimmune transmigrants in Irian Jaya, Indonesia. Am J Trop Med Hyg 52: 479484.
  2. World Health Organization, 2006. Guidelines for the Treatment of Malaria, 2nd ed. Geneva, Switzerland: World Health Organization, 5258.
  3. Smithuis F, Kyaw MK, Phe O, Win T, Aung PP, Oo AP, Naing AL, Nyo MY, Myint NZ, Imwong M, Ashley E, Lee SJ, White NJ, , 2010. Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial. Lancet Infect Dis 10: 673681.[Crossref]
  4. Douglas NM, Nosten F, Ashley EA, Phaiphun L, van Vugt M, Singhasivanon P, White NJ, Price RN, , 2011. Plasmodium vivax recurrence following falciparum and mixed species malaria: risk factors and effect of antimalarial kinetics. Clin Infect Dis 52: 612620.[Crossref]
  5. Beutler E, Duparc S, , 2007. Glucose-6-phosphate dehydrogenase deficiency and antimalarial drug development. Am J Trop Med Hyg 77: 779789.
  6. WHO Working Group, 1989. G6PD deficiency. Bull World Health Organ 67: 601611.
  7. Brueckner RP, Ohrt C, Baird JK, Milhous W, Rosenthal PJ, , 2001. 8-aminoquinolines. , ed. Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New Directions in Drug Discovery. Totowa, NJ: Humana Press Inc.
  8. Lysenko AV, , 1960. Use of quinocide in treatment and prophylaxis of vivax malaria. Bull World Health Organ 22: 641662.
  9. Alving AS, , 1954. Clinical treatment of malaria. Recent Adv Med Surg 2: 209218.
  10. Alving AS, Craige B, Jones R, Whorton CM, Pullman TN, Eichelberger L, , 1948. Pentaquine (Sn-13,276), a therapeutic agent effective in reducing the relapse rate in vivax malaria. J Clin Invest 27: 2533.[Crossref]
  11. Craige B, Jones R, Whorton CM, Pullman TN, Alving AS, Eichelberger L, , 1947. Clinical standardization of pamaquine (plasmochin) in mosquito-induced vivax malaria, Chesson strain. Am J Trop Med 27: 309315.
  12. Alving AS, Arnold J, Hockwald RS, Clayman CB, Dern RJ, Beutler E, Cl Flanagan, , 1955. Potentiation of the curative action of primaquine in vivax malaria by quinine and chloroquine. J Lab Clin Med 46: 301306.
  13. Hill DR, Baird JK, Parise ME, Lewis LS, Ryan ET, Magill AJ, , 2006. Primaquine: report from CDC expert meeting on malaria chemoprophylaxis I. Am J Trop Med Hyg 75: 402415.
  14. Earle DP, Bigelow FS, Zubrod CG, Kane CA, , 1948. Studies on the chemotherapy of the human malarias. IX. Effect of pamaquine on the blood cells of man. J Clin Invest 27: 121129.[Crossref]
  15. Atchley JA, Yount EH, , 1948. Reactions observed during treatment with pentaquine, administered with quinacrine (atabrine) metachloridine (sn-11,437) and with sulfadiazine. J Natl Malar Soc 7: 118124.
  16. Clayman CB, Arnold J, Hockwald RS, Yount EH, Edgcomb JH, Alving A, , 1952. Toxicity of primaquine in caucasians. J Am Med Assoc 149: 15631568.[Crossref]
  17. Craige B, Eichelberger L, Jones R, Alving AS, Pullman TN, Whorton CM, , 1948. The toxicity of large doses of pentaquine (sn-13,276), a new antimalarial drug. J Clin Invest 27: 1724.[Crossref]
  18. Zubrod CG, Kennedy TJ, Shannon J, , 1948. Studies on the chemotherapy of the human malarias; the physiological disposition of pamaquine. J Clin Invest 27: 114120.[Crossref]
  19. Armer RE, Barlow JS, Dutton CJ, Greenway D, Greenwood S, Lad N, Thompson AP, Thong K, Tommasini I, , 1998. 8-aminoquinolines as anticoccidials—II. Bioorg Med Chem Lett 8: 14871492.[Crossref]
  20. Bates MB, Meshnick SR, Sigler CI, Leland P, Hollingdale MR, , 1990. In vitro effects of primaquine and primaquine metabolites on exoerythrocytic stages of Plasmodium berghei . Am J Trop Med Hyg 42: 532537.
  21. Li XQ, Anders Bjorkman AE, Andersson TB, Gustafsson LL, Collen AE, Masimirembwa M, , 2003. Identification of human cytochrome P450s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur J Clin Pharmacol 59: 429442.[Crossref]
  22. Available at: http://www.merckmanuals.com/professional/print/lexicomp/primaquine.html.
  23. Cuong BT, Binh VQ, Dai B, Duy DN, Lovell CM, Rieckmann KM, Edstein MD, , 2006. Does gender, food or grapefruit juice alter the pharmacokinetics of primaquine in healthy subjects? Br J Clin Pharmacol 61: 682689.[Crossref]
  24. Seden K, Dickinson L, Khoo S, Back D, , 2010. Grapefruit–drug interactions. Drugs 70: 23732407.[Crossref]
  25. Constantino L, Paixão 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: 299303.[Crossref]
  26. Frisher H, Meillovitz RL, Ahmad T, Nora MV, , 1991. The conversion of primaquine to primaquine-aldehyde, primaquine-alcohol, and carboxyprimaquine, a major plasma metabolite. J Lab Clin Med 117: 468476.
  27. Ganesan S, Tekwani BL, Sahu R, Tripathi LM, Walker LA, , 2009. Cytochrome P450-dependent toxic effects of primaquine on human erythrocytes. Toxicol Appl Pharmacol 241: 1422.[Crossref]
  28. FDA, 2006. Guidance for Industry Drug Interaction Studies—Study Design, Data Analysis, and Implications for Dosing and Labeling. Rockville, MD: FDA.
  29. Available at: http://www.merckmanuals.com/professional/print/lexicomp/quinine.html. Accessed June 5, 2011.
  30. Projean D, Baune B, Farinotti R, Flinois J, Beaune P, Taburet A, Ducharme J, , 2003. In vitro metabolism of chloroquine: identification of Cyp2c8, Cyp3a4, and Cyp2d6 as the main isoforms catalyzing N-desethylchloroquine formation. Drug Metab Dispos 31: 748754.[Crossref]
  31. Available at: http://www.merckmanuals.com/professional/print/lexicomp/chloroquine.html. Accessed June 5, 2011.
  32. Huang Y, Okochi H, May B, Legname G, Prusiner SB, Benet LZ, Guglielmo BJ, Lin ET, , 2006. Quinacrine is mainly metabolized to mono-desethyl quinacrine by CYP3A4/5 and its brain accumulation is limited by p-glycoprotein. Drug Metab Dispos 34: 11361144.[Crossref]
  33. Karamanakos PN, Trafalis DT, Geromichalos GD, Pappas P, Harkitis P, Konstandi M, Marselos M, , 2009. Inhibition of rat hepatic CYP2E1 by quinacrine: molecular modeling investigation and effects on 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced mutagenicity. Arch Toxicol 83: 571580.[Crossref]
  34. Edwards G, Mcgrath CS, Ward SA, Supanaranond W, Pukrittayakamee S, Davis TME, White NJ, , 1993. Interactions among primaquine, malaria infection and other antimalarials in Thai subjects. Br J Clin Pharmacol 35: 193198.[Crossref]
  35. Brewer GJ, Tarlow AR, Kellermeyer RW, Alving AS, , 1962. The hemolytic effect of primaquine. XV. Role of methemoglobin. J Lab Clin Med 59: 905916.

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  • Received : 01 Aug 2011
  • Accepted : 13 Sep 2011

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