Biotransformation of the antipsychotic agent, mazapertine, in dog--mass spectral characterization and identification of metabolites.
1. Biotransformation of the antipsychotic agent, mazapertine, was studied after a single oral administration of 14C-mazapertine succinate (10 mg/kg, free base) to six beagle dogs (three male, three female). 2. Following oral administration of 14C-mazapertine, plasma (0-48 h), urine (0-7 days), and faeces (0-7 days) were collected. Recoveries of total radioactivity in urine and faeces were 26.9 and 62.0% of the dose, respectively. 3. Unchanged mazapertine plus 14 metabolites were isolated and identified, which accounted for > 60% of the sample radioactivity in the plasma, 17% of the dose in urine and 28% of the dose in faecal extract. 4. Unchanged mazapertine accounted for < 4% of the radioactive dose in excreta samples and < 21% of the sample radioactivity present in plasma samples. 5. Seven metabolic pathways for the formation of metabolites were identified including: (1) phenyl hydroxylation, (2) piperidyl oxidation, (3) O-dealkylation, (4) N-dephenylation, (5) oxidative N-debenzylation, (6) depiperidylation and (7) conjugation. 6. Pathways 1, 2, 5 and 6 produced 4-OH-piperidyl, OH-phenyl-OH-piperidyl, carboxybenzoyl piperidine and depiperidyl analogues of mazapertine as major metabolites.
Wu
W N
WN
Division of Preclinical Development, The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477, USA.
McKown
L A
LA
Takacs
A R
AR
Jones
W J
WJ
Reitz
A B
AB
D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D010879:Piperazines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics
D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; D010879:Piperazines; C086897:mazapertine succinate