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

Abstract

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 (51)Cr-labeled erythrocytes in rats, MAQ-NOH was hemolytic in vivo. Furthermore, in vitro exposure of (51)Cr-labeled erythrocytes to MAQ-NOH caused a concentration-dependent decrease in erythrocyte survival (EC(50) of 350 microM) 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.

• Authors: L J Bolchoz, R A Budinsky, D C McMillan, D J Jollow
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 297 Issue 2 Pg. 509-15 (May 2001) ISSN: 0022-3565 [Print] United States
• PMID: 11303037 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 6-methoxy-8-hydroxylaminoquinoline
• Antimalarials
• Quinolines
• Methemoglobin
• Primaquine

Topics

• Anemia, Hemolytic (blood, chemically induced)
• Animals
• Antimalarials (pharmacokinetics, toxicity)
• Biotransformation
• Chromatography, High Pressure Liquid
• Erythrocyte Aging (drug effects)
• Hematologic Diseases (blood, chemically induced)
• Humans
• In Vitro Techniques
• Magnetic Resonance Spectroscopy
• Male
• Mass Spectrometry
• Methemoglobin (metabolism)
• Microsomes, Liver (metabolism)
• Oxidation-Reduction
• Primaquine (pharmacokinetics, toxicity)
• Quinolines (metabolism, toxicity)
• Rats
• Rats, Sprague-Dawley