RESUMEN
Evaluation of skeletal muscle tolerance during development of new drug formulations for i.m. use is most often based on terminal methods performed in the target species after slaughtering. The objective of this study was to evaluate the effect of muscle damage on the pharmacokinetic parameters of the drug delivered into the muscle using an alternative, noninvasive method. Phenylbutazone (PBZ) was used as the test article. Six ewes received increasing volumes of a 20% PBZ i.m. formulation, according to a cross-over design, and an i.v. bolus of the same formulation. Serial blood samples were taken, and a pharmacokinetic analysis of the plasma activity of creatine kinase and plasma PBZ concentrations was carried out. The amount of muscle damage after i.m. administration of 2, 4, or 8 mL of PBZ, calculated from the area under the curve of plasma creatine kinase across time was 36, 76, and 178 g for a 70-kg ewe. The corresponding absolute bioavailability of PBZ was 100 +/- 32%, 96 +/- 19%, and 100 +/- 17%, and the maximal PBZ concentrations were 42 +/- 3.4, 74 +/- 8.8, and 119 +/- 18.2 microg/mL. The plasma clearance of PBZ (i.v.) was 4.2 +/- 0.94 mL.kg(-1).h(-1). In conclusion, the absolute bioavailability of PBZ after i.m. administration was not altered by the increased volume of formulation administered despite the overall increase in the extent of muscle damage.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Fenilbutazona/administración & dosificación , Fenilbutazona/efectos adversos , Ovinos , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Disponibilidad Biológica , Química Farmacéutica , Creatina Quinasa/sangre , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Inyecciones Intramusculares , Músculo Esquelético , Fenilbutazona/farmacocinética , Distribución AleatoriaRESUMEN
The aim of this study was to assess cyclooxygenase (COX)-1 and COX-2 expression in skeletal muscle after an ischemia-reperfusion (I/R). Male Sprague-Dawley rats were subjected to unilateral hindlimb ischemia for 2 h and then euthanized after 0, 1, 2, 4, 6, 10, 24, and 72 h of reperfusion. The COX protein and mRNA were assessed in control and injured gastrocnemius muscle. Muscle damage was indirectly determined by plasma creatine kinase activity and edema by weighing wet muscle. Creatine kinase activity in plasma increased as early as 1 h after reperfusion and returned to control levels by 72 h of reperfusion. Edema was observed at 6 and 10 h of reperfusion, but histological investigations showed an absence of tissular inflammatory cell infiltration. COX-1 mRNA was expressed in control muscle and was increased at 72 h of reperfusion, but the levels of associated COX-1 protein detected in control and injured gastrocnemius muscle were similar. COX-2 mRNA was not, or only slightly, detectable in control muscle and after I/R. In contrast, I/R induced major overexpression of COX-2 immunoreactivity at 6 and 10 h of reperfusion with a maximum at 10 h, whereas COX-2 protein was undetectable in control muscle. In conclusion, hindlimb I/R induced a large overexpression of COX-2 but not COX-1 protein between 6 and 10 h after injury. These results suggest a role for COX-2 enzyme in such pathophysiological conditions of the skeletal muscle.
Asunto(s)
Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Miembro Posterior/metabolismo , Proteínas de la Membrana/metabolismo , Músculo Esquelético/metabolismo , Daño por Reperfusión/metabolismo , Animales , Femenino , Cinética , Tasa de Depuración Metabólica , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVES: To investigate and validate noninvasive methods for the quantitative evaluation of postinjection muscle damage. ANIMALS: 5 adult sheep. PROCEDURES: Muscle lesions were induced twice in the lumbar region of the longissimus dorsi muscles (2 sides) by IM administration of a 20% formulation of long-acting oxytetracycline (20 mg/kg of body weight). Clinical signs and local cutaneous temperature above the injection site were recorded. Muscle lesions were quantitatively evaluated by ultrasonography and by use of pharmacokinetic analysis of plasma creatine kinase activity, and both were compared with a comprehensive planimetric computer-assisted analysis of the injection sites after euthanasia. RESULTS: Transient cutaneous hypothermia (temperature change, -3.9+/-0.62 C) and subsequent persistent hyperthermia (3.1+/-1.35 C) were observed after the administrations. Despite coefficient of variation < 10% for precision of ultrasonographic measurement of normal muscle, measurements of the lesions, with coefficient of variation > 60% for precision, were systematically underestimated. Quantitative evaluation of muscle damage by use of pharmacokinetic analysis of creatine kinase (12.1+/-4.96 g) was in agreement with results of macroscopic planimetric evaluation (10.8+/-3.64 g). CONCLUSIONS AND CLINICAL RELEVANCE: Ultrasonography cannot be used for quantitative assessment of postinjection muscle damage. Pharmacokinetic analysis of creatine kinase provides an accurate quantitative evaluation of macroscopic muscle damage after IM administration of drugs.