An In vivo Drug Screening Model Using Glucose-6-Phosphate Dehydrogenase Deficient Mice to Predict the Hemolytic Toxicity of 8-Aminoquinolines

Abstract

Abstract. Anti-malarial 8-aminoquinolines drugs cause acute hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDD). Efforts to develop non-hemolytic 8-aminoquinolines have been severely limited caused by the lack of a predictive in vivo animal model of hemolytic potential that would allow screening of candidate compounds. This report describes a G6PDD mouse model with a phenotype closely resembling the G6PDD phenotype found in the African A-type G6PDD human. These G6PDD mice, given different doses of primaquine, which used as a reference hemolytic drug, display a full array of hemolytic anemia parameters, consistently and reproducibly. The hemolytic and therapeutic indexes were generated for evaluation of hemotoxicity of drugs. This model demonstrated a complete hemolytic toxicity response to another known hemolytic antimalarial drug, pamaquine, but no response to non-hemolytic drugs, chloroquine and mefloquine. These results suggest that this model is suitable for evaluation of selected 8-AQ type candidate antimalarial drugs for their hemolytic potential.

Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials

“…Large inter- and intra-individual variation was also observed in reticulocyte counts without consistent differences between PQ-treated and non-treated individuals or between G6PDd and G6PD-normal individuals. Reticulocytosis is potentially an important marker for acute hemolysis and reticulocyte counts were elevated following various doses of PQ in an in vivo drug screening model using G6PDd mice [ 46 ]. We aimed to obtain further insights in hemolysis after PQ by measuring LDH, released from hemolysed red blood cells, and haptoglobin, which binds to hemoglobin released during intravascular or extravascular hemolysis.…”

G6PD deficiency: a classic example of pharmacogenetics with on‐going clinical implications

“…The mouse has a splicing mutation in the G6PD gene (Sanders et al , 1997 ), and it has been used extensively to investigate the possible role of G6PD with respect to cardiovascular disorders (Matsui et al , 2006 ). It appeared that this mutant mouse did not develop drug-induced AHA [(personal communication from the late Ulrich Bienzle of the Institute of Tropical Medicine, Berlin)]; however, very recently Zhang et al ( 2013 ) have achieved AHA in these mice by administering PQ, although at much higher doses (per body weight) than are used therapeutically in humans. Thus, it appears that an outright knock-out of G6PD is too drastic, whereas in the available mutant mice G6PD deficiency is rather mild.…”

Brief Report: Hydroxychloroquine does not induce hemolytic anemia or organ damage in a “humanized” G6PD A- mouse model

“…Some studies suggest that HCQ can be safely administered in the setting of G6PD deficiency [ 2 , 3 ]. In a retrospective chart review of 275 rheumatology patients taking HCQ chronically, 11 African American patients with G6PD deficiency were evaluated through 700 months of therapy, without evident complications [ 2 ].…”

“…In a retrospective chart review of 275 rheumatology patients taking HCQ chronically, 11 African American patients with G6PD deficiency were evaluated through 700 months of therapy, without evident complications [ 2 ]. Additionally, chloroquine did not induce hemolysis in a heterozygote knock-out murine model of G6PD deficiency with 14% residual enzyme activity [ 3 ]; however, the model’s specific hypomorphic mutation is not present in humans.…”