ABSTRACT
Single oral and intramuscular doses of 14C-sultopride to rat, rabbit and dog and single oral doses of sultopride to human volunteers were well absorbed. Mean blood levels of total 14C peaked at 0.4-1.1 h and declined with half-lives of 2, 1.5 and 3 h in rat, rabbit and dog, respectively. In man mean serum levels of unchanged drug attained a peak at 1.5 h and were eliminated with a half-life of 3.6 h. Highest concn. of radioactivity were found in rat liver, kidney, hypophysis, submaxillary gland and gastrointestinal tract. The concn. in the cerebrum and cerebellum were low. 14C-Sultopride passed through the placental barrier. 14C-Sultopride was poorly bound to plasma proteins (less than 25% bound) in all species. Repeated doses of the drug slightly increased the blood and tissue levels of 14C in the rat. Most of the dose was eliminated via the kidneys in all species. Male rats excreted larger amounts of 14C into bile and faeces. A high ratio of A.U.C. (milk)/(blood) (c. 3.5) was found in the lactating rat.
Subject(s)
Sulpiride/analogs & derivatives , Absorption , Adult , Amisulpride , Animals , Dogs , Female , Humans , Kidney/metabolism , Male , Milk/metabolism , Pregnancy , Protein Binding , Rabbits , Rats , Sulpiride/metabolism , Tissue DistributionABSTRACT
The biotransformation of sultopride has been investigated in rat, rabbit, dog and man. In man sultopride was metabolically stable, and about 90% of an oral dose was excreted in urine unchanged and 4% as oxo-sultopride. Rat, rabbit and dog metabolized sultopride more extensively and excreted less than 40% of an oral dose of 14C-sultopride in urine. Four similar metabolites were excreted by the three animal species but the relative portions differed. The major radioactive component in rat urine was O-desmethyl sultopride, whereas oxo-sultopride and O-desmethyl sultopride were the major urinary metabolites in rabbit. Dog formed N-desethyl sultopride and oxo-sultopride as major urinary metabolites. The male rat excreted smaller amounts of unchanged sultopride in urine than did the female rat. The unchanged sultopride excreted in rat urine was increased slightly by repeated administration.
Subject(s)
Psychotropic Drugs/metabolism , Sulpiride/analogs & derivatives , Amisulpride , Animals , Bile/metabolism , Biotransformation , Brain/metabolism , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Dogs , Female , Humans , Male , Methylation , Oxidation-Reduction , Psychotropic Drugs/blood , Psychotropic Drugs/urine , Rabbits , Rats , Scintillation Counting , Sulpiride/blood , Sulpiride/metabolism , Sulpiride/urineABSTRACT
The disposition of aprindine following a single oral dose can best be described by a two-compartment open model. The mean plasma half-life (t 1/2 beta) increased from 8.0 +/- 2.1 h (SD) after a 25 mg dose of 9.4 +/- 2.9 h after 50 mg and to 15.8 +/- 2.6 h after 100 mg, with a decrease in total plasma clearance (Cl/F) and volume of distribution at steady state (V dss/F) and during beta-phase (V d beta/F). The area under plasma concentration-time curve (AUC), maximum plasma concentration (C max) and the amount of unchanged aprindine excreted in the urine increased in a non-linear fashion with the increase in dose. The t 1/2 beta after multiple oral doses showed a 3-fold increase over the single dose value. These results indicate that aprindine shows dose-dependent non-linear kinetics.
Subject(s)
Aprindine/metabolism , Indenes/metabolism , Adult , Aprindine/administration & dosage , Blood Proteins/metabolism , Dose-Response Relationship, Drug , Half-Life , Humans , Kinetics , Male , Protein BindingSubject(s)
Aprindine/blood , Indenes/blood , Adult , Gas Chromatography-Mass Spectrometry , Humans , Male , Time FactorsABSTRACT
1. 1-Hexylcarbamoyl-5-fluoro[6-14C]uracil (14C-HCFU) administered orally to rats, rabbits and dogs at a dose of 20 mg/kg was well absorbed and rapidly excreted via the kidney. 2. HCFU was extensively biotransformed, and its six metabolites including two new metabolites were detected in plasma and urine of all three species. Two new metabolites were identified by spectral analysis as 1-(5-hydroxyhexylcarbamoyl)5-fluorouracil and 1-(5-oxohexylcarbamoyl)-5-fluorouracil. 3. The metabolic pathways of HCFU in the three species involved oxidations and scission of the side-chain with successive degradation of the fluorouracil (FU) released. 4. The two main routes of oxidations of the side chain were omega-oxidation and omega-1-oxidation. Rats metabolized HCFU preferentially by the former reaction, while in rabbits and dogs the latter reaction predominated.
Subject(s)
Fluorouracil/analogs & derivatives , Absorption , Animals , Antineoplastic Agents/metabolism , Dogs , Fluorouracil/blood , Fluorouracil/metabolism , Fluorouracil/urine , Kinetics , Male , Oxidation-Reduction , Rabbits , Rats , Species SpecificityABSTRACT
1. The metabolic fate of a new antitumour agent, 1-hexylcarbamoyl-5-fluoro [6-14C]uracil (14C-HCFU) in rats after oral administration was compared with that of 5-fluoro[6-14C]uracil (14C-FU). 2. Tissue radioactivity reached a max. 1 to 3 h after administration of 14C-HCFU and 0.5 h after 14C-FU. 3. Both drugs were excreted rapidly, mostly in urine. Expired 14CO2 from 14C-HCFU was significantly less than that from 14C-FU. 4. Unchanged FU was not detected in plasma 3 h after administration of 14C-FU, whereas FU was detected in plasma 5 h after 14C-HCFU. The pyrimidine ring of 14C-HCFU might be degradated more slowly than that of 14C-FU. 5. 1-(5-Carboxypentylcarbamoyl)-5-fluorouracil and 1-(3-carboxypropylcarbamoyl)-5-fluorouracil were identified as the major urinary metabolites of 14C-HCFU.
