Physicochemical, pharmacokinetic and pharmacodynamic evaluation of liposomal tacrolimus (FK 506) in rats.
OBJECTIVE
Tacrolimus (FK 506) is a new potent immunosuppressant. Because of poor water solubility, the conventional intravenous dosage forms of FK 506 (C-FK 506) contain surfactants such as HCO-60 which may cause adverse effects. We sought a liposomal formulation of FK 506 (L-FK 506) containing endogenous phospholipids to target drug to the spleen, a major organ controlling the immune system.


METHODS
L-FK 506, consisting of 0.1 micron diameter vesicles of phosphatidylcholine and phosphatidylglycerol (molar ratio 9:1) and 7.5 mole% drug, was evaluated for in vitro stability. The intravenous disposition profile, spleen distribution, and immunosuppression of L-FK 506 was compared with that of C-FK 506 in the rat after single doses of 0.3 mg/kg.


RESULTS
The L-FK 506 showed good in vitro stability. L-FK 506 exhibited an increased volume of distribution at steady-state (Vss) (from 3.41 to 14.71 L/kg) and increased mean residence time (MRT) (from 2.83 to 16.07 hr). FK 506 concentrations in spleen were increased by 40% at 10 hr after administration of the liposomal formulation. The pharmacodynamics of L-FK 506, evaluated by the extent of inhibition of splenocyte proliferation, was comparable to that of C-FK 506.


CONCLUSIONS
Liposomal FK 506 may be an improved dosage form for parenteral use.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008081:Liposomes; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D012996:Solutions; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D016559:Tacrolimus / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D008081:Liposomes; D012996:Solutions; D016559:Tacrolimus