Pharmacokinetic and immunosuppressive effects of tacrolimus-loaded biodegradable microspheres

✍ Scribed by Yasunori Miyamoto; Takeji Uno; Hiromitsu Yamamoto; Li Xiao-Kang; Koh-ichi Sakamoto; Hisakuni Hashimoto; Hirofumi Takenaka; Yoshiaki Kawashima; Hideo Kawarasaki

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 91 KB
• Volume: 10
• Category: Article
• ISSN: 1527-6465
• DOI: 10.1002/lt.20083

✦ Synopsis

The objective of this study was to characterize the pharmacokinetics and immunosuppression of a tacrolimusloaded biodegradable microsphere (TLBM) in rats. We prepared TLBM. DA/Slc rats were given TLBM at a dose of 1.6 mg/kg (n ‫؍‬ 9), 2.4 mg/kg (n ‫؍‬ 5), or 7.2 mg/kg (n ‫؍‬ 7) tacrolimus contents by a single subcutaneous administration to achieve sustained release over a long period. DA/Slc rats were given TLBM by a single subcutaneous administration at a dose of 4.8 mg/kg (n ‫؍‬ 6) tacrolimus contents to clarify the main site of TLBM uptake in the organs. In the rat liver transplantation model, the recipients were given TLBM at a dose of 0.16 mg/kg (n ‫؍‬ 5), 2.4 mg/kg (n ‫؍‬ 4), or 4.8 mg/kg (n ‫؍‬ 5) tacrolimus contents by a single subcutaneous administration on the first day after operation. Overall survival days were compared. Continuous flat parallel concentration profiles were significant for 10 days from the first day after a single subcutaneous administration of TLBM (P < .01). The relationship between the dosages of TLBM administration and area under the concentration-time curve (AUC) up to 18 days demonstrated a linear regression line (P < .01). In addition, the relationship between the dose of TLBM and the survival days of the recipients in the liver transplantation model showed a positive correlation. The current pharmacokinetic study of TLBM revealed significantly increased tacrolimus levels in the regional lymph nodes compared with other organs except bone marrow (P < .01). In conclusion, TLBM allowed tacrolimus to release gradually in a very stable manner for 10 days, with dose-dependent immunosuppression after a single subcutaneous administration. The main site of TLBM uptake after subcutaneous administration was the regional lymph node of administration site. (Liver