Biodistribution and pharmacokinetics of O-palmitoyl tilisolol, a lipophilic prodrug of tilisolol, after intravenous administration in rats.
The purpose of this study was to modify the biodistribution and pharmacokinetics of tilisolol, a beta-blocker, using the palmitoyl prodrug approach. After intravenous administration of tilisolol and O-palmitoyl tilisolol in rats, drug concentrations were determined in blood, bile, urine, and several tissues. The concentration-time profiles of tilisolol and O-palmitoyl tilisolol were analyzed pharmacokinetically. The blood concentrations of O-palmitoyl tilisolol after intravenous administration of O-palmitoyl tilisolol were about 10-fold higher than those of tilisolol after intravenous administration of tilisolol. The biliary excretion rates of O-palmitoyl tilisolol and tilisolol after intravenous administration of O-palmitoyl tilisolol were about 10- to 100-fold larger than those of tilisolol after intravenous administration of tilisolol. In addition, the hepatic uptake clearance of O-palmitoyl tilisolol after intravenous administration of O-palmitoyl tilisolol was 3.6-fold higher than that of tilisolol after the intravenous administration of tilisolol. In the in vitro experiments, it was demonstrated that the distribution ratios between blood cells and plasma (blood/plasma) of O-palmitoyl tilisolol and tilisolol was 95.7 and 55.5%, respectively. These findings suggest that O-palmitoyl tilisolol exists as a binding form with biological components, especially blood cells, in systemic circulation. In conclusion, the palmitoyl prodrug approach is useful as a drug delivery system to deliver the parent drug to the liver.
Kawakami
Shigeru
S
School of Pharmaceutical Sciences, Nagasaki University, Japan. kawakami@net.nagasaki-u.ac.jp
Ohshima
Nao
N
Hirayama
Ryu
R
Al
Masami Hi
MH
Kitahara
Takashi
T
Sakaeda
Toshiyuki
T
Mukai
Takahiro
T
Nishida
Koyo
K
Nakamura
Junzo
J
Nakashima
Mikiro
M
Sasaki
Hitoshi
H
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D007275:Injections, Intravenous; D007546:Isoquinolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D007546:Isoquinolines; D011355:Prodrugs; C036593:tilisolol