Pharmacokinetics and amoebicidal activity of (+-)-(E)-3-(4- methylsulphinylstyryl)-1,2,4-oxadiazole (BTI 2286E) and its sulphone metabolite (BTI 2571E) in the golden hamster, Mesocricetus auratus.
BTI 2286E is a 1,2,4-oxadiazole with amoebicidal activity. Three groups of golden hamsters received single doses of BTI 2286E or its sulphone metabolite BTI 2571E as either BTI 2286E 60 mg/kg po or BTI 2571E 60 mg/kg po or BTI 2571E 60 mg/kg ip. Blood samples were collected up to 8 h post-dose and plasma concentrations of BTI 2286E and BTI 2571E were assayed by HPLC. BTI 2286E was rapidly absorbed, extensively metabolized during first pass and rapidly eliminated with a plasma elimination half-life of 1.32 h. Conversion to BTI 2571E was the major pathway of elimination. BTI 2571E had approximately 40% bioavailability after oral administration. After intraperitoneal administration its absorption was slow and prolonged, with an apparent elimination half-life of 2.77 h, considerably longer than the elimination half-life of 0.67 h observed when BTI 2571E was formed as a metabolite, in vivo. The amoebicidal activity of both the compounds was evaluated in the acute hamster hepatic model of amoebiasis. Both BTI 2286E and BTI 2571E were administered as single graded po or ip dose, and their dose-response profiles were characterized. BTI 2571E exhibited poor activity after oral administration (ED50 70 mg/kg) probably due to poor bioavailability, but after intraperitoneal administration its activity (ED50 40 mg/kg) was comparable to that of BTI 2286E after po or ip administration.
Pargal
A
A
Research Division, Boots Pharmaceuticals Limited, Bombay, India.
Kelkar
M G
MG
Bhopale
K K
KK
Phaltankar
P G
PG
Kaul
C L
CL
D000284:Administration, Oral; D000563:Amebicides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000818:Animals; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004748:Entamoeba histolytica / Q000187:drug effects / Q000254:growth & development; D006207:Half-Life; D007274:Injections, Intraperitoneal; D008101:Liver Abscess, Amebic / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D008647:Mesocricetus; D010069:Oxadiazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013450:Sulfones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013454:Sulfoxides / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000563:Amebicides; D010069:Oxadiazoles; D013450:Sulfones; D013454:Sulfoxides; C084183:3-(4-methylsulfinylstyryl)-1,2,4-oxadiazole; C084184:3-(4-methylsulfonylstyryl)-1,2,4-oxadiazole