title: Effect of pharmacokinetic profile on the pancreatic toxicity and efficacy of tacrolimus in rats.
abstract: The aim of this study is to investigate the effect of the pharmacokinetic profile of tacrolimus on its pancreatic toxicity and efficacy in rats. For toxicity evaluation, doses of 0.03, 0.1, or 0.3 mg/kg/day were given once daily for 8 days in the bolus intravenous injection groups. In the continuous intravenous infusion groups, tacrolimus was infused using an Alzet osmotic mini-pump for 9 days at the same doses. Pancreatic insulin content decreased dose-dependently in both the bolus intravenous injection and continuous intravenous infusion groups, and there was no significant difference between the decreases caused by the two dosing regimens. At 0.03 mg/kg, continuous intravenous infusion did not cause glucose intolerance, but bolus intravenous injection induced significant and dose-dependent glucose intolerance. The pharmacokinetic data indicated that continuous intravenous infusion resulted in a sustained blood drug concentration with an area under the curve (AUC) similar to that obtained with the bolus administration at the same dose. For efficacy evaluation, donor ear grafts were transplanted to the lateral thoraxes of recipients. Tacrolimus doses of 0.01, 0.1, or 1 mg/kg/day were administered from day 0 to day 13. Both bolus intramuscular administration and continuous intravenous infusion prolonged skin allograft survival dose-dependently, and there was no significant difference between the median survival times of groups given the same doses. To summarize, the sustained-release of tacrolimus resulted in a steady blood drug concentration with an AUC similar to that of the bolus administration. In rats, it was better tolerated and just as efficacious as the bolus administration without producing a higher maximal blood concentration (Cmax). These results indicate that the sustained-release formulation has the potential to improve the safety of tacrolimus.
authors.affiliation: Drug Safety Research Laboratories, Astellas Pharma Inc., Osaka, Japan. takashi.mitamura@jp.astellas.com
authors.forename: Takashi
authors.initials: T
authors.lastname: Mitamura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamada
authors.forename: Kaori
authors.initials: K
authors.lastname: Hanaoka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Asano
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niwa
authors.forename: Jiro
authors.initials: J
authors.lastname: Seki
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005951:Glucose Tolerance Test; D006084:Graft Rejection / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D007262:Infusions, Intravenous; D007273:Injections, Intramuscular; D007328:Insulin / Q000378:metabolism; D008297:Male; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D016038:Skin Transplantation; D016559:Tacrolimus / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D001786:Blood Glucose; D007166:Immunosuppressive Agents; D007328:Insulin; D016559:Tacrolimus