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.
Miyamoto
Yasunori
Y
Division of Hospital Pharmacy, Hamamatsu University School of Medicine, Shizuoka, Japan. ymiyamo@hama-med.ac.jp
Uno
Takeji
T
Yamamoto
Hiromitsu
H
Xiao-Kang
Li
L
Sakamoto
Koh-Ichi
K
Hashimoto
Hisakuni
H
Takenaka
Hirofumi
H
Kawashima
Yoshiaki
Y
Kawarasaki
Hideo
H
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