PT  - JOURNAL ARTICLE
AU  - Laura J. C. Bolchoz
AU  - Robert A. Budinsky
AU  - David C. McMillan
AU  - David J. Jollow
TI  - Primaquine-Induced Hemolytic Anemia: Formation and Hemotoxicity of the Arylhydroxylamine Metabolite 6-Methoxy-8-hydroxylaminoquinoline
DP  - 2001 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 509--515
VI  - 297
IP  - 2
4099  - http://jpet.aspetjournals.org/content/297/2/509.short
4100  - http://jpet.aspetjournals.org/content/297/2/509.full
SO  - J Pharmacol Exp Ther2001 May 01; 297
AB  - 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. SinceN-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. The American Society for Pharmacology and Experimental Therapeutics