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. 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.
Footnotes
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Send reprint requests to: David C. McMillan, Ph.D., Department of Pharmacology, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425. E-mail: mcmilldc{at}musc.edu
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↵1 Present address: B.B.L., Inc., 1203 Governor's Square Blvd., 6th Floor, Tallahassee, FL 32301.
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This study was supported by National Institutes of Health Grants HL-3008 and DK-47423.
- Abbreviations:
- G6PD
- glucose-6-phosphate dehydrogenase
- 6-MAQ
- 6-methoxy-8-aminoquinoline
- MAQ-NOH
- 6-methoxy-8-hydroxylaminoquinoline
- DMSO
- dimethyl sulfoxide
- PBSG
- phosphate-buffered saline supplemented with glucose
- MS/MS
- tandem mass spectrometry
- ESI
- electrospray ionization
- HPLC-EC
- high performance liquid chromatography with electrochemical detection
- Received September 6, 2000.
- Accepted January 16, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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