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Oral delivery of liposomal tacrolimus: increased efficacy and reduced toxicity
Oral Delivery of Liposomal Tacrolimus: Increased Efficacy and Reduced Toxicity V.C. McAlister, M. Keshavamurthy, and T.D.G. Lee
I
NTRAVENOUS administration of liposomal amphotericin and other liposomal drugs has been required to prevent liposome disruption and maintain the protective effect of encapsulation. We and others have made liposomal tacrolimus (TAC) and have shown how this alters drug pharmacokinetics, biodisposition, and effect.1–3 We hoped to develop a liposomal preparation that firmly bound TAC and would thereby be stable in the GI tract and absorbed intact. METHOD Liposomal tacrolimus (LTAC) was made using a modification of the solvent evaporation method. For biodisposition studies, 3H and 14 C were used to label TAC and the phosphatidylcholine (DPPC) component of the liposome, respectively. BALB/c mice were given, by gavage, one dose (0.5 mg/kg) of TAC or LTAC. Drug and DPPC levels were measured at 24 and 96 hours in blood and various tissues. Efficacy was tested using skin transplantation between BALB/c and C57bl/6 mice and heterotopic heart transplantation between BN and Lewis rats. Glomerular filtration rate was measured by 3H-inulin clearance in Wistar rats following 3 days of TAC or LTAC (10 mg/kg per day, by gavage).
RESULTS
Oral LTAC had 25% better absorption than TAC and drug penetration of all organs, including liver, kidney, spleen, and brain, at both 24 and 96 hours, was increased by fourto fivefold. In all cases, the drug was accompanied by an equivalent amount of DPPC, indicating that it remained liposome bound. Doses of 1 mg/kg per day for 5 days prolonged skin graft survival for LTAC, but not TAC
0041-1345/99/$–see front matter PII S0041-1345(98)01923-X
(control, 6.3 6 2.3 days; TAC, 7.2 6 3.2; LTAC, 11.6 6 3.6, P , .05). Low-dose (0.25 mg/kg per day indefinitely) LTAC, but not TAC, delayed skin graft rejection (TAC, 8.2 6 3.4 days; LTAC, 11.4 6 2.9 days). LTAC, but not TAC, was able to reverse rejection in a model where treatment was delayed until day 5. BN heterotopic hearts in Lewis rats survived indefinitely (.60 days; control, 8 days) with either LTAC or TAC (1 mg/kg per day for 5 days). Inulin clearance was preserved in LTAC- (21.5 6 2.0% reduction compared with control), but not in TAC-treated rats (65.0 6 1.2% reduction). DISCUSSIONS
These data are similar to those seen after intravenous administration of LTAC. LTAC made by this method appears to be absorbed intact by the gastrointestinal tract. It may be more efficacious and less toxic than commercial TAC. REFERENCES 1. McAlister VC: Transplant Proc 30:1000, 1998 2. Ko S, Nakajima Y, Kanehiro H, et al: Transplantation 59:1384, 1995 3. Lee M, Straubinger RM, Jusko WJ: Pharm Res 12:1055, 1995 From the Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada. Address reprint requests to Vivian McAlister, 8813 Victoria Wing, QEII Health Sciences Centre, Halifax, Nova Scotia B3H 2Y9, Canada. E-mail: [email protected].
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1110
Transplantation Proceedings, 31, 1110 (1999)
I
NTRAVENOUS administration of liposomal amphotericin and other liposomal drugs has been required to prevent liposome disruption and maintain the protective effect of encapsulation. We and others have made liposomal tacrolimus (TAC) and have shown how this alters drug pharmacokinetics, biodisposition, and effect.1–3 We hoped to develop a liposomal preparation that firmly bound TAC and would thereby be stable in the GI tract and absorbed intact. METHOD Liposomal tacrolimus (LTAC) was made using a modification of the solvent evaporation method. For biodisposition studies, 3H and 14 C were used to label TAC and the phosphatidylcholine (DPPC) component of the liposome, respectively. BALB/c mice were given, by gavage, one dose (0.5 mg/kg) of TAC or LTAC. Drug and DPPC levels were measured at 24 and 96 hours in blood and various tissues. Efficacy was tested using skin transplantation between BALB/c and C57bl/6 mice and heterotopic heart transplantation between BN and Lewis rats. Glomerular filtration rate was measured by 3H-inulin clearance in Wistar rats following 3 days of TAC or LTAC (10 mg/kg per day, by gavage).
RESULTS
Oral LTAC had 25% better absorption than TAC and drug penetration of all organs, including liver, kidney, spleen, and brain, at both 24 and 96 hours, was increased by fourto fivefold. In all cases, the drug was accompanied by an equivalent amount of DPPC, indicating that it remained liposome bound. Doses of 1 mg/kg per day for 5 days prolonged skin graft survival for LTAC, but not TAC
0041-1345/99/$–see front matter PII S0041-1345(98)01923-X
(control, 6.3 6 2.3 days; TAC, 7.2 6 3.2; LTAC, 11.6 6 3.6, P , .05). Low-dose (0.25 mg/kg per day indefinitely) LTAC, but not TAC, delayed skin graft rejection (TAC, 8.2 6 3.4 days; LTAC, 11.4 6 2.9 days). LTAC, but not TAC, was able to reverse rejection in a model where treatment was delayed until day 5. BN heterotopic hearts in Lewis rats survived indefinitely (.60 days; control, 8 days) with either LTAC or TAC (1 mg/kg per day for 5 days). Inulin clearance was preserved in LTAC- (21.5 6 2.0% reduction compared with control), but not in TAC-treated rats (65.0 6 1.2% reduction). DISCUSSIONS
These data are similar to those seen after intravenous administration of LTAC. LTAC made by this method appears to be absorbed intact by the gastrointestinal tract. It may be more efficacious and less toxic than commercial TAC. REFERENCES 1. McAlister VC: Transplant Proc 30:1000, 1998 2. Ko S, Nakajima Y, Kanehiro H, et al: Transplantation 59:1384, 1995 3. Lee M, Straubinger RM, Jusko WJ: Pharm Res 12:1055, 1995 From the Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada. Address reprint requests to Vivian McAlister, 8813 Victoria Wing, QEII Health Sciences Centre, Halifax, Nova Scotia B3H 2Y9, Canada. E-mail: [email protected].
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1110
Transplantation Proceedings, 31, 1110 (1999)