Subacute Toxicity And Toxicokinetics Of Injection With Dexlansoprazole

Objective:Lansoprazole is a proton pump inhibitor(proton pump inhibitors,PPIs),which can be used in the treatment of gastroesophageal reflux disease(gastroesophageal reflux disease,GERD).Dexlansoprazole is the dextro-enantiomers of lansoprazole,and can be used for patients with duodenal ulcer with bleeding that are not suitable for oral therapy.This study followed the guidelines for preclinical toxicity studies of drugs to study the acute toxicity,subacute toxicity and pharmacokinetics of dexlansoprazole in rats.And to evaluate the toxicity of the dexlansoprazole for injection and find out the target organs.Thus to provide a theoretical basis for the follow-up studies.Also,a comparison study with lansoprazole for injection,a marketed drug,was performed to provides reference information for clinical safety medication and adverse reaction monitoring.Methods:1.Acute toxicity studyAccording to the principle of acute toxicity experimental design,the dosage for both dexlansoprazole for injection and lansoprazole for injection were 250.0,225.0,202.5,182.3,164.0 and 0 mg/kg respectively.The 10 SD rats(5 males and 5 females)in each group were intravenously administered.General behavior,adverse effects and mortality were recorded for up to 14 days post treatment.LD50 and 95%confidential intervals were measured.2.Subacute toxicity studyDexlansoprazole for injection was given intravenously at the dose of 60,20,6,and 0 mg/kg per day(n=20/group each sex)for 4 weeks to rats.Lansoprazole for injection with a dose of 60mg/kg were administered simultaneously.Clinical symptoms after treatment were observed.3.Toxicokinetics studyThe 80 SD rats(8 per group each sex)were randomly divided into five groups including three administration of different dose(60,20,6)mg/kg,injection with lansoprazole(60mg/kg)and injection with S-lansoprazole(60mg/kg).Blood samples of each animal were collected on the 1st and 28th day at before and 0,0.083,0.5,1,2,4 and 6 hours after the treatment.The concentration of the dexlansoprazole and lansoprazole in plasma was determined by LC-MS/MS.And the toxicokinetics parameters were calculated with DAS2.1.1 program.Results:1.Acute toxicityThe(LD50)of intravenous administration of dexlansoprazole and lansoprazole in rats is 207.17mg/kg(95%confidence interval 196.66--218.30 mg/kg)and 206.61mg/kg(95%confidence interval 195.46-218.74 mg/kg)respectively.During the 14-day study,the general condition of the animals was good,and the body weight gain showed not effected.No further signs of toxicity occurred,and no abnormality of organs noted in histopathological examinations.2.Subacute toxicityThere were no significant changes in body weight gain,food intake,biochemical parameters,coagulation time,serum electrolyte measurement and etc.in rats at dexlansoprazole 20mg/kg.And slight atrophy was found in thymuses but recoverable while treatment stopped at this dosage.EOS%and MCV changed significant in rats treated with both 60 mg/kg dexlansoprazole and lansoprazole.In the dexlansoprazole 60 mg/kg dose group,a sign of neurological symptom was observed in male rats right after administration.The same symptoms also found in female rats in the beginning 9 days after dosage,and which disappeared from the 10th day.But the female rats showed hair loss on the back then,and recovered one week advance in the end of recovery period.A weight loss of thymuses occurred in both 60 mg/kg dexlansoprazole and lansoprazole treated animal groups,and can be recovered to some extent in the recovery period.3.Toxicokinetics study:The results showed concentration in serum reached peak at 5 min post treatment,and decreased afterward rapidly.The AUC(0-t),AUC(0-∞)and Cmax of all dexlansoprazole dosage treated rats were observed significantly increased after 28-day administration compared to the single dose treatment.Suggested dexlansoprazole exposure ascension obviously after 4 weeks treatment in both male and female rats.Related analysis lead to a resulted that the toxicokinetic parameters has a linear relationship with dosages both in single and repeated dexlansoprazole treated rats.Conclusion:The relative safe dose of intravenous administration for 4 weeks of the dexlansoprazole for injection was not more than 20 mg/kg/day in rats,and thymus is the main target organ.The toxicity in both acute and subacute studies with dexlansoprazole and lansoprazole are similar.Characteristics of linear toxicokinetics of dexlansoprazole in female and male rats were discovered.This study provided important information for the monitoring toxicity and adverse effects therefore to applicate safely clinically of the dexlansoprazole for injection.