The Study Of Oral Gavage Chronic Toxicity And Toxicokinetic With Propranolol Hydrochloride In Beagle

Propranolol is a sympatholytic beta blocker earliest used in clinical treatment.The mechanism of propranolol is to nonselective block β1 and β2 receptor,depress heart contraction and atrioventricular conduction,reduce cardiac output and myocardial oxygen consumption,inhabit rennin releasing,diastolic peripheral vascular,which was widely used to treat hypertension,tachycardia,cardiomyopathy,angina,etc.In later decades years,with some new pharmacological effects have been found that the drug is also used for treatment of neonatal hemangioma,migraine,psychiatric diseases.In long-term application,various side effects in cardiovascular,nervous system and also in other aspect had been reported.OBJECTIVE:The purpose of this study was to evaluate the toxicity and determine the toxicokinetics of the test article,propranolol hydrochloride(also known as propranolol)when administered once daily via oral gavage to dogs for at least 13 weeks and to assess the reversibility,persistence,or delayed occurrence of any effects after a 4-week recovery phase according to cFDA GLP regulations.METHED:Dogs were randomly assigned to four groups of 6 with 3 in each gender,control group(0 mg/kg)and 3 dose group,low(4 mg/kg),middle(12mg/kg),and high dose(30mg/kg)group.Animals were dosed via oral gavage for 13 weeks and then followed by 4 weeks’ recovery period.Assessment of toxicity was based on mortality,clinical observations,body weights,food consumption,vital signs,blood pressure determination,ophthalmic and electrocardiogram(ECG)examinations,and clinical and anatomic pathology.According to survival situation,Blood samples were collected for hematology,clinical chemistry and toxicokinetic evaluations,and also,urine were collected for urinalysis on day 1,day 27 and day 85.RESULT:One male given 30 mg/kg/day died accidentally following dosing on Day 16 of the dosing phase.Macroscopic and microscopic findings in this animal along with death following dosing suggested this animal likely died due to a gavage error.All remaining animals survived until their scheduled sacrifice.Vomitus and fecal observations were noted in females given 12 or 30 mg/kg/day and in males at all dose levels,with much higher incidence and longer duration in treated males.Therefore,vomitus and fecal observations were considered test article-related.Administration of propranolol at 4,12,or 30 mg/kg/day resulted in decreased heart rate at 1 to 2 hours postdose on Day 90 of the dosing phase.The decrease in heart rate was minimal,did not display a relationship to dose,and was not noted on Day 27 of the recovery phase.The decrease in heart rate was an expected pharmacologic action of propranolol.No other propranolol related ECG changes were noted.After oral administration,propranolol was readily observed in plasma and propranolol plasma concentration was decreased after reaching Cmax.Systemic exposure of propranolol(assessed by Cmax and AUC0-24h)generally increased with increasing dose.No marked(>2-fold)sex differences were observed in mean Cmax or AUC0-24h values.Generally,values for Cmax and AUC0-24h did not appear to change after multiple doses,indicating no accumulation of propranolol.In conclusion,after 13 weeks’ gavage administration and 4 weeks’ recovery period,no death was found due to drug;beside vomitus and soft feces,no other clinical finding was observed;no abnormal symptoms was found in ophthalmology examination,ECG.No drug related body weight change,organ weight change,macroscopic and microscopic change;no abnormal finding was noted in hematology,coagulation,biochemistry and urological analysis.So under the dose level,the no observed adverse effect level(NOAVEL)is 30 mg/kg/day.The dose level of 30mg/kg/day also corresponded to an AUC0-24h 8120 ng·hr/mL in males and 8000 ng·hr/mL in females on Day 85 of the dosing phase.