Mv. Shirbacheh et al., Pharmacokinetic advantage of intra-arterial cyclosporin A delivery to vascularly isolated rabbit forelimb. II. dose dependence, J PHARM EXP, 289(3), 1999, pp. 1191-1195
Citations number
19
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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.