AN IMPROVED PHARMACODYNAMIC MODEL FOR FORMATION OF METHEMOGLOBIN BY ANTIMALARIAL-DRUGS

The widely used 8-aminoquinoline antimalarial group of compounds and t he derivatives such as WR242511 that are being developed for possible prophylactic anticyanide applications have complex interactions with e rythrocytes. Methemoglobin (MetHb) levels following the use of this dr ug predicted by earlier authors grossly deviated from the observed ste ady state levels under multiple-dose conditions. We propose a pharmaco kinetic-pharmacodynamic model to characterize literature data for bloo d levels of MetHb generated after administration of WR242511. The mode l is based on an indirect mechanism involving WR242511 putative metabo lite concentration, C-m on the formation of MetHb (rate constant, k(r) ) and on depletion of reducing equivalents leading to accumulation of MetHb, Eventual depletion of MetHb is modeled as related to the dispos ition of both the drug metabolite and MetHb. The rate of change of Met Hb concentration in the blood under the influence of a dose of WR24251 1 in dogs was governed by this relationship: d[MetHb]/d(t) = k(r) . C- m . [Hb] - k(h) . [MetHb], where k(r) is 2.9 x 10(-5) ml . ng(-1) . hr (-1) and k(h) is 0.0418 hr(-1). This model was validated with multiple -dose data. The model is simple and compatible with the physiological behavior of MetHb in vivo under single-dose and multiple-dose conditio ns of WR242511 administration.