title: Pharmacokinetics and pharmacodynamics of the myotoxic venom of Pseudechis australis (mulga snake) in the anesthetised rat.
abstract: BACKGROUND
  Myotoxicity is a common clinical effect of snake envenoming and results from either local or systemic myotoxins in snake venoms. Although numerous myotoxins have been isolated from snake venoms, there has been limited study on the relationship between the time course of venom concentrations (pharmacokinetics) and the time course of muscle injury measured as a rise in creatine kinase (CK) (pharmacodynamics).
  
  
  OBJECTIVE
  The aim of this study was to develop an in vivo model of myotoxicity to investigate the time course of myotoxicity and the effect of antivenom.
  
  
  METHODS
  Anesthetised rats were administered Pseudechis australis (mulga snake) venom either through i.v., i.m. or s.d. route, including a range of doses (5-100 μg/kg). Serial blood samples were collected for measurement of venom using enzyme immunoassay and measurement of CK and creatinine. Antivenom was administered before, 1 and 6 h after venom administration to investigate its effect on muscle injury. Plots of venom and CK versus time were made and the area under the curve (AUC) was calculated.
  
  
  RESULTS
  There was a significant dose-dependent increase in CK concentration after administration of P. australis venom, which was greatest for i.v. administration. Timed measurement of venom concentrations showed a rapid absorption through s.d. and i.m. routes and a delayed rise in CK concentrations following any route. Antivenom prevented myotoxicity shown by a decrease in the CK AUC, which was most effective if given earliest. There was a rise in creatinine following i.v. venom administration.
  
  
  CONCLUSIONS
  The study shows the delayed relationship between venom absorption and the rise in CK, consistent with the delayed onset of myotoxicity in human envenoming. Antivenom prevented myotoxicity more effectively if given earlier.
authors.affiliation: Department of Pharmacology, Monash Venom Group, Monash University , Victoria , Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Hart
authors.forename: W C
authors.initials: WC
authors.lastname: Hodgson
authors.forename: M
authors.initials: M
authors.lastname: O'Leary
authors.forename: G K
authors.initials: GK
authors.lastname: Isbister
mesh_terms: D000818:Animals; D052283:Creatine Kinase, MM Form / Q000097:blood; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004546:Elapid Venoms / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D017815:Elapidae; D007124:Immunoenzyme Techniques; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000293:injuries; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004546:Elapid Venoms; C026235:Pseudechis venom; D003404:Creatinine; D052283:Creatine Kinase, MM Form
keywords: Antivenom; Creatine kinase; Myotoxicity; Pharmacokinetics; Snake toxins; Venom