Pharmacokinetic advantage of intra-arterial cyclosporin A delivery to vascularly isolated rabbit forelimb. II. Dose dependence

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

Research output: Contribution to journalArticle

12 Scopus citations

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. cyclosporin A (CSA) administration. CSA was infused continuously via osmotic minipump into the right brachial artery of New Zealand rabbits at multiple doses ranging from 1.0 to 8.0 mg/kg/day. On day 6, CSA concentrations were measured in aortic whole blood, as well as in skin, muscle, bone, and bone marrow samples from both right and left forelimbs. The variation of right-sided mean CSA concentrations with dose was tissue dependent and saturable in the case of skin and bone, whereas left-sided tissue concentrations correlated significantly with systemic blood levels. At 1.0 mg/kg/day, there were no significant differences between right and left mean CSA concentrations for all four tissues examined. However, with a doubling of the i.a. dose, huge increases in local tissue CSA concentrations were produced with only very modest increases in systemic whole-blood and tissue drug levels, resulting in a 4-fold regional advantage (right/left ratio of CSA concentrations) in bone and bone marrow, 7-fold in muscle, and 14-fold in skin. With further dose increases to 8.0 mg/kg/day, the regional advantage decreased to 4-fold in skin, increased to 9-fold in bone marrow, remained relatively constant in bone, and initially decreased and then increased to 9-fold in muscle. These favorable pharmacokinetic results suggest that reduced, local doses of CSA might be useful in preventing extremity composite tissue allograft rejection with decreased systemic drug exposure.

Original languageEnglish (US)
Pages (from-to)1191-1195
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Volume289
Issue number3
StatePublished - Jun 1 1999
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Shirbacheh, M. V., Harralson, T. A., Jones, J. W., Breidenbach, W. C., Jevans, A. W., Maldonado, C., Barker, J. H., & Gruber, S. A. (1999). Pharmacokinetic advantage of intra-arterial cyclosporin A delivery to vascularly isolated rabbit forelimb. II. Dose dependence. Journal of Pharmacology and Experimental Therapeutics, 289(3), 1191-1195.