Abstract
We developed a water-in-oil-in-water (W/O/W)-type multiple emulsion of a new tacrolimus formulation. A potential approach to avoid the complications of systemic immunosuppression and simultaneously enhance immunosuppressive efficacy is to deliver immunosuppressive agents locally to the site of the target organs. The W/O/W emulsion is dispersed oil drops containing smaller water droplets that allow the delivery of drugs preferentially to the reticuloendothelial system (RES). Since the liver and the spleen are primary components of the RES, and the brain and the kidney have a poor RES, we hypothesized that a W/O/W emulsion of tacrolimus would prossess the pharmacokinetic benefits of local immunosuppression. We evaluated this hypothesis in a rat model. The tacrolimus levels of whole blood, the liver, spleen, brain, and kidney in rats given intravenous emulsions of tacrolimus (W/O/W group) were compared with a group administered tacrolimus alone (T group). There were no significant differences between the pharmacokinetic parameters of W/O/W group and T group based on whole blood data. However, the W/O/W group had significantly decreased tacrolimus levels in the brain and kidney, and significantly increased levels in the liver and spleen compared with the T group. These data suggest that the W/O/W emulsion is applicable as an intravenous drug carrier for local immunosuppression.
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Abbreviations
- AUC:
-
area under the concentration time curve
- β:
-
apparent elimination rate constant
- β:
-
phase apparent volume of the distribution
- CLtot :
-
total clearance
- Cp :
-
whole blood tacrolimus concentration
- GE:
-
glycerol fatty acid ester
- RES:
-
reticuloendothelial system
- TEM:
-
transmission electron microscope
- t1/2β :
-
biological half-life of the elimination phase
- Vc :
-
apparent volume of the central compartment
- Vd(β), W/O/W:
-
water-in-oil-in-water
References
Kino, T., Hatanaka, H., Miyata, S., Inamura, N., Nishiyama, M., Yajima, T., Goto, T., Okuhara, M., Kohsaka, M., Aoki, H., and Ochiai, T. (1987) FK-506, a Novel Immunosuppressant Isolated from a Streptomyces II. Immunosuppressive Effect of FK-506 in vitro, J. Antibiotics 40, 1256–1265.
Todo, S., Fung, J.J., Starzl, T.E., Tzakis, A., Demetris, A.J., Kormos, R., Jain, A., Alessiani, M., Takaya, S., and Shapiro, R. (1990) Liver, Kidney, and Thoracic Organ Transplantation under FK 506, Ann. Surg. 212, 295–307.
The US Multicenter FK506 Liver Study Group (1994) A Comparison of Tacrolimus (FK 506) and Cyclosporine for Immunosuppression in Liver Transplantation, N. Engl. J. Med. 331, 1110–1115.
Benoy, C.J., Elso, L.A., and Schneider, R. (1972) Multiple Emulsions, a Suitable Vehicle to Provide Sustained Release of Cancer Chemotherapeutic Agents, Br. J. Pharmacol. 45, 135–136.
Brodin, A.F., Kavaliunas, D.R., and Frank, S.G. (1978) Prolonged Drug Release from Multiple Emulsions, Acta Pharm. Suec. 15, 1–12.
Takahashi, T., Ueda, S., Kono, K., and Majima, S. (1976) Attempt at Local Administration of Anticancer Agents in the Form of Fat Emulsion, Cancer 38, 1507–1514.
Herbert, W.J. (1965) A New Form of Mineral-Oil Antigen Adjuvant, Lancet 2, 771–771.
Gruber, S.A. (1992) The Case for Local Immunosuppression, Transplantation 54, 1–11.
Aebischer, P., Lacy, P.E., Gerasimidi-Vazeou, A., and Hauptfeld, V. (1991) Production of Marked Prolongation of Islet Xenograft Survival (Rat to Mouse) by Local Release of Mouse and Rat Antilymphocyte Sera at Transplant Site, Diabetes 40, 482–485.
Bolling, S.F., Lin, H., Annesley, T.M., Boyd, J.A., Gallagher, K.P., and Levy, R.J. (1991) Local Cyclosporine Immunotherapy of Heart Transplants in Rats Enhances Survival, J. Heart Lung Transplant. 10, 577–583.
Freise, C.E., Liu, T., Hong, K., Osorio, R.W., Demetris, A.J., Ferrell L., Ascher, N.L., and Roberts, J.P. (1994) The Increased Efficacy and Decreased Nephrotoxicity of a Cyclosporine Liposome, Transplantation 57, 928–932
Ko, S., Nakajima, Y., Kanehiro, H., Horikawa, M., Yoshimura, A., Taki, J., Aomatsu, Y., Kin, T., Yagura, K., and Nakano, H. (1995) The Enhanced Immunosuppressive Efficacy of Newly Developed Liposomal FK506 in Canine Liver Transplantation, Transplantation 59, 1384–1388.
Tamura, K., Kobayashi, M., Hashimoto, K., Nagase, K., Iwasaki, K., Kaizu, T., Tanaka, H., and Niwa, M. (1987) A Highly Sensitive Method to Assay FK-506 Levels in Plasma, Transplant. Proc. 19, 23–29.
Okabe, S. (1981) Drug Eruption by Solution Trioxyethylene Hydrogenated Castor Oil (HCO-60) in Vitamin K2, Jpn. J. Dematol. 91, 759–762.
Ohta, S., Iwane, S., Katsura, T., Shimada, M., and Hayashi, S. (1985) Leukocytosis Induced by BH-AC Administration. Allergic Reaction to Castor Oil HCO-60, Jpn. J. Clin. Hematol. 26, 555–559.
Lee, M.J., Straubinger, R.M., and Jusko, W.J. (1995) Physicochemical, Pharmacokinetic and Pharmacodynamic Evaluation of Liposomal Tacrolimus (FK 506) in Rats, Pharm. Res. 12, 1055–1059.
Ko, S., Nakajima, Y., Kanehiro, H., Yoshimura, A., and Nakano, H. (1994) The Pharmacokinetic Benefits of Newly Developed Liposome-Incorporated FK506, Transplantation 58, 1142–1144.
Steiner, J.P., Dawson, T.M., Fotuhi, M., Glatt, C.E., Snowman, A.M., and Snyder, N. (1992) High Brain Densities of the Immunophilin FKBP Colocalized with Calcineurin, Nature 358, 584–587.
McCarley, J., Fung, J.J., Todo, S., Jain, A., Deballi, P., and Starzl, T.E. (1991) Changes in Renal Function After Liver Transplantation under FK 506, Transplant. Proc. 23, 3143–3145.
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Uno, T., Yamaguchi, T., Li, X.K. et al. The pharmacokinetics of water-in-oil-in-water-type multiple emulsion of a new tacrolimus formulation. Lipids 32, 543–548 (1997). https://doi.org/10.1007/s11745-997-0069-1
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DOI: https://doi.org/10.1007/s11745-997-0069-1