Appraisal of the intramuscular irritation test in the rabbit.

Musculoirritancy testing in the rabbit has been recognized as sufficiently sensitive to be highly predictive of human tolerance for intramuscularly administered drugs. A three-part study consisting of gross characterization of the lesion, microscopic observation and determination of serum activity of the enzyme creatine phosphokinase (CPK) has evolved as a standard test for evaluating single injection injury in the muscle. Injection and tissue processing procedures are described as well as a revised grading system for gross examination based on degrees of necrosis and hemorrhage, respectively. Based on 213 determinations, the control mean serum CPK activity was 262 +/- 113 I.U./liter. The importance of pretest acclimation of rabbits in establishing this value was emphasized. Designations of slight, moderate, or marked irritation are based on accumulative scoring of all rabbits at postinjection intervals of 1, 3, and 7 days. At 24 hr postinjection, serum CPK activities up to and including a range of 2000-3000 I.U./liter have been shown to be compatible with slight irritation and are considered predictive of human tolerance.