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 β-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

PEGylated Liposomes Loading Palmitoyl Prednisolone for Prolonged Blood Concentration of Prednisolone

We investigated the pharmacokinetic behavior of palmitoyl prednisolone (Pal-PLS) and its liposomes with L-α-distearoylphosphatidylcholine (DSPC) and cholesterol (Chol) with or without L-α-distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG 2000) after their intravenous administration in rats. Pal-PLS rapidly disappeared from the systemic circulation and prednisolone (PLS) was regenerated after the administration of DSPC/Chol liposomes. PEGylated liposomes including DSPE-PEG 2000, however, successfully maintained high blood concentrations of Pal-PLS and PLS. The blood profiles of drugs after the administration of liposomal Pal-PLS were analyzed according to a two-compartment model. The larger content of DSPE-PEG 2000 in DSPC/Chol liposomes showed a lower first order elimination rate constant from the central compartment (Kel) and clearance (CL). The area under the concentration?time curve (AUC) of Pal-PLS and PLS in PEGylated liposomes was larger than DSPC/Chol liposomes. The mean resident time (MRT) of Pal-PLS and PLS was also prolonged by PEGylated liposomes. Although DSPC/Chol liposomes showed a high distribution of Pal-PLS in the liver and spleen, PEGylated liposomes significantly decreased the liver distribution of Pal-PLS. The biliary and urinary excretions of drugs for 240 min after drug administration were less than 1% of the administrated dose in any formulations. In conclusion, PEGylated liposomes, including Pal-PLS, are useful for maintain the PLS concentration in the blood after intravenous administration