BIOAVAILABILITY OF SKELETAL-MUSCLE CREATI NE-KINASE IN SHEEP - APPLICATION TO THE ASSESSMENT OF LOCAL TOLERANCE TO VETERINARY DRUGS

Pharmacokinetic variables of skeletal muscle creatine kinase were dete rmined in sheep after intravenous and intramuscular administration of the semipurified enzyme. Catheters implanted in the jugular vein were used for both intravenous injections and blood withdrawals. Blood samp le collection by vacutainer and hemolysis may in fact have considerabl e effects on the measurement of creatine kinase activity in plasma. Th e change in the enzyme activity versus time in the plasma, after intra venous administration (123 +/- 38 U/kg of creatine kinase, was fitted by a biexponential model. The mean volume of the central compartment ( 45 +/- 5 mL/kg) was approximately equal to the plasma volume. Plasma h alf-life and plasma clearance of creatine kinase were 3.7 +/- 1.7 h an d 23 +/- 8 mL.kg(-1).h(-1), respectively. Mean plasma bioavailability of creatine kinase after intramuscular administration (357 +/- 36 U/kg ) in both the loins and the gluteal mass was 42%. Maximal plasma activ ity was observed 4 and 5 h after injection and the half-life of the te rminal phase was 7.3 or 8.6 h according to the muscle. The extent of m uscle damage after intramuscular administrations of 21 veterinary drug formulations (one product per animal) was estimated from the total cr eatine kinase activity released in plasma during the 72 h following th e injection. Equivalent weights of damaged muscle ranged from 1.4 to 8 3.3 g according to the irritant potency of the test formulation Result s differed only moderately between the injection sites (right and left gluteal mass) in the same animal. It can be concluded from this study that, in sheep: i) the bioavailability of creatine kinase from differ ent infection sites (gluteal mass and loins) is comparable; and ii) th e intra-individual variability in the estimation of muscle damage is m oderate. Once validated, this non-invasive approach for local toleranc e studies could be of value in assessing and comparing the irritant po tency of veterinary drugs and in reducing the number of animals requir ed.