title: Pharmacokinetics, metabolism and excretion of megazol in a Trypanosoma brucei gambiense primate model of human African trypanosomiasis. Preliminary study.
abstract: 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.
authors.affiliation: Laboratoire de Cinétique des Xénobiotiques, Faculté des Sciences Pharmaceutiques, Toulouse, France.
authors.forename: B
authors.initials: B
authors.lastname: Enanga
authors.forename: J M
authors.initials: JM
authors.lastname: Ndong
authors.forename: H
authors.initials: H
authors.lastname: Boudra
authors.forename: L
authors.initials: L
authors.lastname: Debrauwer
authors.forename: G
authors.initials: G
authors.lastname: Dubreuil
authors.forename: B
authors.initials: B
authors.lastname: Bouteille
authors.forename: G
authors.initials: G
authors.lastname: Chauvière
authors.forename: C
authors.initials: C
authors.lastname: Labat
authors.forename: M
authors.initials: M
authors.lastname: Dumas
authors.forename: J
authors.initials: J
authors.lastname: Périé
authors.forename: G
authors.initials: G
authors.lastname: Houin
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier; D002522:Chlorocebus aethiops; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D005260:Female; D006207:Half-Life; D008297:Male; D013830:Thiadiazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D014344:Trypanocidal Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D014347:Trypanosoma brucei gambiense; D014353:Trypanosomiasis, African / Q000378:metabolism* / Q000469:parasitology
chemical_list: D013830:Thiadiazoles; D014344:Trypanocidal Agents; C013378:megazol