RT Journal Article
SR Electronic
T1 Primaquine-Induced Hemolytic Anemia: Susceptibility of Normal versus Glutathione-Depleted Rat Erythrocytes to 5-Hydroxyprimaquine
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 79
OP 85
DO 10.1124/jpet.103.062984
VO 309
IS 1
A1 Zachary S. Bowman
A1 John E. Oatis, Jr.
A1 Jennifer L. Whelan
A1 David J. Jollow
A1 David C. McMillan
YR 2004
UL http://jpet.aspetjournals.org/content/309/1/79.abstract
AB Primaquine is an important antimalarial agent because of its activity against exoerythrocytic forms of Plasmodium spp. Methemoglobinemia and hemolytic anemia, however, are dose-limiting side effects of primaquine therapy. These hemotoxic effects are believed to be mediated by metabolites, although the identity of the toxic specie(s) and the mechanism underlying hemotoxicity have remained unclear. Previous studies showed that an N-hydroxylated metabolite of primaquine, 6-methoxy-8-hydroxylaminoquinoline, was capable of mediating primaquine-induced hemotoxicity. The present studies were undertaken to investigate the hemolytic potential of 5-hydroxyprimaquine (5-HPQ), a phenolic metabolite that has been detected in experimental animals. 5-HPQ was synthesized, isolated by flash chromatography, and characterized by NMR spectroscopy and mass spectrometry. In vitro exposure of 51Cr-labeled erythrocytes to 5-HPQ induced a concentration-dependent decrease in erythrocyte survival (TC50 of ca. 40 μM) when the exposed cells were returned to the circulation of isologous rats. 5-HPQ also induced methemoglobin formation and depletion of glutathione (GSH) when incubated with suspensions of rat erythrocytes. Furthermore, when red cell GSH was depleted (>95%) by titration with diethyl maleate to mimic GSH instability in human glucose-6-phosphate dehydrogenase deficiency, a 5-fold enhancement of hemolytic activity was observed. These data indicate that 5-HPQ also has the requisite properties to contribute to the hemotoxicity of primaquine. The relative contribution of N-hydroxy versus phenolic metabolites to the overall hemotoxicity of primaquine remains to be assessed. The American Society for Pharmacology and Experimental Therapeutics