Primaquine-induced hemolytic anemia: formation and hemotoxicity of the arylhydroxylamine metabolite 6-methoxy-8-hydroxylaminoquinoline.
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.
Bolchoz
L J
LJ
Department of Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Budinsky
R A
RA
McMillan
D C
DC
Jollow
D J
DJ
D000743:Anemia, Hemolytic / Q000097:blood / Q000139:chemically induced*; D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics / Q000633:toxicity*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004905:Erythrocyte Aging / Q000187:drug effects; D006402:Hematologic Diseases / Q000097:blood / Q000139:chemically induced*; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008706:Methemoglobin / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D011319:Primaquine / Q000493:pharmacokinetics / Q000633:toxicity*; D011804:Quinolines / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
C425886:6-methoxy-8-hydroxylaminoquinoline; D000962:Antimalarials; D011804:Quinolines; D008706:Methemoglobin; D011319:Primaquine