Pharmacokinetics, metabolism and excretion of megazol in a Trypanosoma brucei gambiense primate model of human African trypanosomiasis - Preliminary study

The pharmacokinetics of megazol (2-amino-5-(1-methyl-5-nitro-2-imidazolyl)- 1,3,4-thiadiazol, CAS 19622-55-0) was investigated after a 100 mg/kg oral a dministration to six primates infected with Trypanosoma brucei gambiense. T he plasma levels of megazol were between 0.2 mu g/ml and 46 mu g/ml 24 h af ter dosing in all animals. In animals with prolonged infection, megazol abs orption was accelerated (T-max was 4 h compared with 8 h, for day 53 and da y 39 post inoculation) but the amount absorbed was not modified. The megazo l concentrations in the cerebrospinal fluid represented between 5.5 % and 1 0.6 %, of the plasma levels at the same rimes. Unchanged megazol was elimin ated predominantly via the kidneys: 46-96 % of the ingested dose was recove red in the urine, compared with 0-5 % in the faeces. Furthermore, this urin ary elimination of megazol was altered in animals with prolonged infections . In the urine, 4 unknown metabolites were observed, unchanged megazol was characterized by LC-MS/MS. This study indicates that megazol crosses the bl ood-brain barrier after oral administration. Prolonged infections affect th e absorption of megazol and its urinary elimination.