title: Non-invasive and quantitative evaluation of post-injection muscle damage by pharmacokinetic analysis of creatine kinase release.
abstract: Intramuscular administration of veterinary drugs can induce severe muscle damage resulting in economic losses and residue persistence. Local tolerance is usually evaluated by macroscopic examination of the injection site requiring euthanasia of a large number of animals. A non-invasive quantitative method, based on the pharmacokinetic analysis of creatine kinase (CK) release from muscle, is proposed for the evaluation of post-injection muscle damage. Plasma CK activity is a specific and sensitive marker of skeletal muscle damage. Three disposition parameters are needed to measure the actual amount of CK released by the injured muscle: plasma CK clearance, bioavailability of CK from muscle and area under the plasma CK activity vs time curve. A CK solution from a homologous muscle extract was administered in different animal species by intravenous route and by intramuscular route for the determination of the CK disposition parameters. The general equation for the determination of the destroyed muscle equivalent (Q), following the drug intramuscular injection, is: Q = CI x AUC/F x M, with Cl, the plasma CK clearance; AUC, the area under the plasma CK vs time curve after drug administration; F, the CK bioavailability from muscle; and M, the CK content in the injected muscle. Population equations are proposed for dogs, sheep, horses and cattle and their use is illustrated. Rabbits and pigs seem inappropriate species for the pharmacokinetic approach because of stress-induced spontaneous increases in plasma CK. In cattle, for example, Q (g.kg-1 body weight) = 4.4 x 10(-6) AUC (U.h.L-1) and the estimated equivalent of muscle destroyed after a single IM injection of a chloramphenicol formulation was about 300 g. This screening approach is simple, ethical, rapid and inexpensive.
authors.affiliation: Unité de physiopathologie et toxicologie expérimentales et département des sciences biologiques et fonctionnelles, Inra, Ecole nationale vétérinaire de Toulouse, France.
authors.forename: H P
authors.initials: HP
authors.lastname: Lefebvre
authors.forename: V
authors.initials: V
authors.lastname: Laroute
authors.forename: J P
authors.initials: JP
authors.lastname: Braun
authors.forename: V
authors.initials: V
authors.lastname: Lassourd
authors.forename: P L
authors.initials: PL
authors.lastname: Toutain
mesh_terms: D000818:Animals; D001682:Biological Availability; D015415:Biomarkers / Q000097:blood; D002417:Cattle; D003402:Creatine Kinase / Q000097:blood* / Q000493:pharmacokinetics; D004285:Dogs; D006736:Horses; D007273:Injections, Intramuscular / Q000009:adverse effects* / Q000662:veterinary; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000201:enzymology / Q000293:injuries* / Q000473:pathology*; D011817:Rabbits; D012756:Sheep; D013552:Swine
chemical_list: D015415:Biomarkers; D003402:Creatine Kinase