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

A vascularly isolated rabbit forelimb model simulating conditions of compos ite 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 ran ging 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 sa mples from both right and left forelimbs. The variation of right-sided mean CSA concentrations with dose was tissue dependent and saturable in the cas e of skin and bone, whereas left-sided tissue concentrations correlated sig nificantly with systemic blood levels. At 1.0 mg/kg/day, there were no sign ificant differences between right and left mean CSA concentrations for all four tissues examined. However, with a doubling of the i.a. dose, huge incr eases in local tissue CSA concentrations were produced with only very modes t 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 i ncreases to 8.0 mg/kg/day, the regional advantage decreased to 4-fold in sk in, increased to g-fold in bone marrow, remained relatively constant in bon e, and initially decreased and then increased to 9-fold in muscle. These fa vorable pharmacokinetic results suggest that reduced, local doses of CSA mi ght be useful in preventing extremity composite tissue allograft rejection with decreased systemic drug exposure.