Absorption, distribution and excretion of [14C]-Lesopitron after single and repeated administration in rats and dogs.
Disposition of [14C]-lesopitron was investigated in male rats and dogs after single and repeated oral administration. Radioactivity was rapidly and efficiently absorbed from gastrointestinal tract following oral administration. After 7 days, the radioactivity was mainly excreted into feces via bile. The cumulative urinary and fecal excretion was 99% and 75% of the administered dose in rats and dogs, respectively. [14C]-Lesopitron was widely distributed in rats, with the highest concentrations in liver and kidney, while the concentration in brain was similar to that in plasma. Radioactivity in most tissues decreased essentially in parallel with that in plasma. In rats, plasma levels of [14C]-lesopitron radioactivity achieved steady state on day 2 of repeated administration. The distribution pattern obtained after 7 consecutive daily oral doses was similar to that in the single-dose study. At 72 h after the last administration, tissue radioactivity was fully eliminated and no accumulation occurred. After i.v. administration in rats and dogs, plasma concentrations of lesopitron decreased biphasically with an apparent elimination half-life of 100 min. The absolute bioavailability of lesopitron was about 10%, suggesting an important first-pass effect. In rats, the lesopitron plasma concentrations were similar to those obtained for its metabolites (5-hydroxylesopitron and PmP), whereas in dogs, the PmP plasma concentrations were higher than those for lesopitron and 5-hydroxylesopitron.
Serafini
M T
MT
Department of Pharmacokinetics and Drug Metabolism, Laboratorios Dr. Esteve, S.A., Barcelona, Spain.
Puig
S
S
García-Encina
G
G
Farran
R
R
García-Soret
A
A
Moragon
T
T
Martínez
L
L
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004285:Dogs; D004333:Drug Administration Routes; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D014151:Anti-Anxiety Agents; D010879:Piperazines; D011743:Pyrimidines; C075568:lesopitron