Pharmacokinetics of intra-arterial delivery of tacrolimus to vascularly isolated rabbit forelimb

Mansour V. Shirbacheh, Jon W. Jones, Thomas A. Harralson, Jean Edelstein, Taskin Tecimer, Warren C Breidenbach, Anthony W. Jevans, Claudio Maldonado, John H. Barker, Scott A. Gruber

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Abstract

A vascularly isolated rabbit forelimb model simulating conditions of composite tissue allografting was used to determine the regional pharmacokinetic advantage achievable in extremity tissue components during i.a. tacrolimus (FK506) administration. FK506 was infused continuously via osmotic minipump into the right brachial artery of New Zealand rabbits at 0.05, 0.1, and 0.2 mg/kg/day. On day 6, FK506 concentrations were measured in aortic whole blood, heart, lung, liver, kidney, spleen, and fat, as well as in skin, muscle, bone, and bone marrow samples from both right and left forelimbs. The relative tissue concentrations of FK506 in descending order were [spleen ≃ lung ≃ kidney] > [heart ≃ skin ≃ muscle] > [fat bone marrow] > [liver ≃ bone ≃ blood]. In marked contrast to previous results with i.a. cyclosporin A infusion, only a minimal regional advantage of local FK506 delivery (mean right/left concentration ratios 1.0-1.4) was obtained in all forearm tissues over the dose range studied. For each limb tissue, left- sided FK506 concentrations significantly correlated with systemic blood levels, and the left-sided tissue-to-whole-blood concentration ratio did not vary significantly with dose. We conclude that FK506 is pharmacokinetically inferior to cyclosporin A for continuous i.a. administration to the vascularly isolated rabbit forelimb, and hypothesize that this difference is the result of differences in the distribution of each drug within whole blood. Our findings suggest that, despite its demonstrated efficacy in experimental and clinical transplantation, FK506 would not be an appropriate immunosuppressant to deliver via the i.a, route for prevention of limb allograft rejection.

Original languageEnglish (US)
Pages (from-to)1196-1201
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume289
Issue number3
Publication statusPublished - Jun 1999
Externally publishedYes

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ASJC Scopus subject areas

  • Pharmacology

Cite this

Shirbacheh, M. V., Jones, J. W., Harralson, T. A., Edelstein, J., Tecimer, T., Breidenbach, W. C., ... Gruber, S. A. (1999). Pharmacokinetics of intra-arterial delivery of tacrolimus to vascularly isolated rabbit forelimb. Journal of Pharmacology and Experimental Therapeutics, 289(3), 1196-1201.