The metabolite patterns of eltoprazine in man, dog, rat and rabbit.
To compare the metabolism of eltoprazine of dog, rat and rabbit with that in man, urine samples were collected after dosing with 14C-eltoprazine. The 14C-labelled metabolites were separated by chromatography and detected by their radioactivity. This resulted in so-called metabolite patterns. The human metabolite pattern contained peaks that were all found in that obtained from the dog's urine. The dog's metabolite pattern had two peaks that were (almost) absent in all other species. The rat's urine gave a pattern which had only two peaks in common with the human pattern. Unchanged drug was excreted in significant amounts by man, dog, and rat, but not by rabbit. This excretion was even a little more pronounced after intravenous injection of the drug. In man, the ratio between unchanged drug and metabolites was fairly constant with time after dosing, while this ratio decreased in the animal species. The major part of the metabolites were sulphate- or glucuronide conjugates, but hydrolysis of these required extraordinary amounts of enzyme. We do not yet know whether the observed species differences reflect differences in conjugating activity or (and) oxidative metabolism. We could not identify important differences in the metabolite patterns that were due to sex or route of drug administration. Also, the site of the 14C-label in the drug molecule hardly affected the metabolite patterns; the only effect was the excretion by the rat of a very polar but minor component when it was dosed with 14C-piperazine labelled eltoprazine. This component was absent when 14C-phenyl labelled eltoprazine was given.
Koster
H J
HJ
Duphar B.V., Drug Disposition Department, Weesp, The Netherlands.
de Greef
L
L
Klerks
F
F
Raghoebar
M
M
D000284:Administration, Oral; D000818:Animals; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004285:Dogs; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007275:Injections, Intravenous; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000378:metabolism* / Q000652:urine; D011817:Rabbits; D051381:Rats; D012727:Sex Characteristics; D013045:Species Specificity; D013431:Sulfates / Q000378:metabolism
D002250:Carbon Radioisotopes; D005965:Glucuronates; D010879:Piperazines; D013431:Sulfates; C063828:eltoprazine