Methemoglobin formation resulting from administration of candidate 8-aminoquinoline antiparasitic drugs in the dog.

In vivo methemoglobin (MHb) formation caused by five 8-aminoquinoline compounds was tested in beagle dogs. Male beagle dogs were dosed orally once per day at 0.0116 mmol/kg for 4 consecutive days with primaquine (8-[4-amino-1-methylbutyl)amino]-6-methoxyquinoline, diphosphate), three candidate 8-aminoquinoline antimalarial drugs (WR 225,448 5-(3-trifluoromethyl)phenoxy-4-methyl primaquine, succinate); WR 238,605 2,6-dimethoxy-5-(3-trifluoromethyl)phenoxy-4-methyl primaquine, succinate; or WR 242,511 5-hexoxy-4-methyl primaquine, diphosphate dihydrate), or a candidate 8-aminoquinoline antileishmanial drug WR 6026 (8-[(6-diethylamino)amino]-6-methoxy-4-methyl quinoline, dihydrochloride). MHb and total hemoglobin levels were determined daily prior to dosing and for 29 days after drug administration. All compounds caused prolonged levels of MHb that peaked at Days 4 to 5 with disappearance half-lives of 5 to 9 days. Peak percentage MHb of primaquine, WR 6026, WR 238,605, WR 225,448, and WR 242,511 was 6.3, 20.7, 16.0, 25.3, and 48.1%, respectively. Total MHb as measured by area under the time-concentration curve was highest for WR 242,511, followed by WR 225,448, WR 238,605, WR 6026, and primaquine, respectively. The results of this study, in conjunction with other toxicity and efficacy studies, have been utilized to select one of these compounds for development as a replacement for the antimalarial drug primaquine, and also to characterize the MHb-forming properties of WR 6026.