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 administration to six primates infected with Trypanosoma brucei gambiense. The plasma levels of megazol were between 0.2 microgram/ml and 46 micrograms/ml 24 h after dosing in all animals. In animals with prolonged infection, megazol absorption was accelerated (Tmax was 4 h compared with 8 h, for day 53 and day 39 post inoculation) but the amount absorbed was not modified. The megazol concentrations in the cerebrospinal fluid represented between 5.5% and 10.6% of the plasma levels at the same times. Unchanged megazol was eliminated predominantly via the kidneys: 46-96% of the ingested dose was recovered in the urine, compared with 0-5% in the faeces. Furthermore, this urinary 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 blood-brain barrier after oral administration. Prolonged infections affect the absorption of megazol and its urinary elimination.