Pharmacokinetic and immunosuppressive effects of tacrolimus-loaded biodegradable microspheres.
The objective of this study was to characterize the pharmacokinetics and immunosuppression of a tacrolimus-loaded 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.
Division of Hospital Pharmacy, Hamamatsu University School of Medicine, Shizuoka, Japan. ymiyamo@hama-med.ac.jp
Yasunori
Y
Miyamoto
Takeji
T
Uno
Hiromitsu
H
Yamamoto
Li
L
Xiao-Kang
Koh-Ichi
K
Sakamoto
Hisakuni
H
Hashimoto
Hirofumi
H
Takenaka
Yoshiaki
Y
Kawashima
Hideo
H
Kawarasaki
D000818:Animals; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007279:Injections, Subcutaneous; D016031:Liver Transplantation / Q000276:immunology / Q000379:methods; D008198:Lymph Nodes / Q000737:chemistry / Q000187:drug effects; D008297:Male; D008863:Microspheres; D051381:Rats; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D007166:Immunosuppressive Agents; D016559:Tacrolimus