Simultaneous and minimally invasive assessment of muscle tolerance and bioavailability of different volumes of an intramuscular formulation in the same animals.
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.
Ferre
P J
PJ
Unité Mixte de Recherche 181 INRA/ENVT, Experimental Pathophysiology and Toxicology, National Veterinary School of Toulouse, 23 Chemin des Capelles, BP 87614, 31076 Toulouse cedex 03, France.
Laroute
V
V
Braun
J P
JP
Cazaux
J
J
Toutain
P L
PL
Lefebvre
H P
HP
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003402:Creatine Kinase / Q000097:blood; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D007273:Injections, Intramuscular; D018482:Muscle, Skeletal; D010653:Phenylbutazone / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D011897:Random Allocation; D012756:Sheep
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003402:Creatine Kinase; D010653:Phenylbutazone