Primaquine-induced hemolytic anemia: Formation and hemotoxicity of the arylhydroxylamine metabolite 6-methoxy-8-hydroxylaminoquinoline

Laura J.C. Bolchoz, Robert A. Budinsky, David C. Mcmillan, David J. Jollow

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56 Scopus citations


Primaquine is an important antimalarial agent because of its activity against exoerythrocytic forms of Plasmodium spp. However, methemoglobinemia and hemolytic anemia are dose-limiting side effects of primaquine therapy that limit its efficacy. These hemotoxicities are thought to be mediated by metabolites; however, the identity of the toxic species has remained unclear. Since N-hydroxy metabolites are known to mediate the hemotoxicity of several arylamines, the present studies were undertaken to determine whether 6-methoxy-8-aminoquinoline (6-MAQ), a known human metabolite of primaquine, could undergo N-hydroxylation to form a hemotoxic metabolite. When 6-MAQ was incubated with rat and human liver microsomes, a single metabolite was detected by high performance liquid chromatography (HPLC) with electrochemical detection. This metabolite was identified as 6-methoxy-8-hydroxylaminoquinoline (MAQ-NOH) by HPLC and mass spectral analyses. As measured by decreased survival of 51Cr-labeled erythrocytes in rats, MAQ-NOH was hemolytic in vivo. Furthermore, in vitro exposure of 51Cr-labeled erythrocytes to MAQ-NOH caused a concentration-dependent decrease in erythrocyte survival (EC50 of 350 μM) when the exposed cells were returned to the circulation of isologous rats. MAQ-NOH also induced the formation of methemoglobin when incubated with suspensions of rat erythrocytes. These data indicate that 6-MAQ can be metabolized to MAQ-NOH by both rat and human liver microsomes and that MAQ-NOH has the requisite properties to be a hemotoxic metabolite of primaquine. The contribution of MAQ-NOH to the hemotoxicity of primaquine in vivo remains to be assessed.

Original languageEnglish (US)
Pages (from-to)509-515
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - 2001
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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