Subchronic toxicity and toxicokinetics of LZB, a new proton pump inhibitor, after 13-week repeated oral administration in dogs.
The subchronic toxicity and toxicokinetics of a novel proton pump inhibitor, pymeprazole (LZB), were investigated in beagle dogs by daily oral administration for 13 consecutive weeks. Three test groups received doses of 30, 100 and 300 mg/kg/day of LZB. Rabeprazole of 60 mg/kg/day was used as positive control. The 13-week repeated oral doses of LZB resulted in objective signs of mild gastrointestinal disturbance for high-dose group animals. One individual dog of high-dose group was found to be lethargy and astasia at the last month of administration; for hematology, mild anemia was observed at high-dose females; for clinical chemistry, higher cholest, trigly and gastrin were observed at high-dose females, higher ASAT, ALAT, cholesterol, triglyceride and gastrin at high-dose males were also observed; for histopathology, the primary effects of LZB were related to gastric mucosa of high-dose group seen by H and E or Grimelius stain. Impairment of surface epithelium was observed by SEM. The treat-related effects basically were reversible for a 4-week drug-free period. As for positive control group, 13-week oral administration of rabeprazole resulted in more severe toxicity than high-dose group of LZB although much lower dose was employed. The accumulation of LZB after 13-week oral administration was not notable at the toxic dose of 300 mg/kg/day. The toxic dose was considered to be 100mg/kg/day and the no-observed-adverse-effect level (NOAEL) to be 30 mg/kg/day, which is much higher than other PPIs. The toxicological target could be stomach, liver, hematological system and nervous system.
Mao
Yu
Y
Center of Evaluation for Drug Safety, Second Military Medical University, Shanghai 200433, China.
Zhang
Xiaodong
X
Li
Li
L
Yuan
Bojun
B
Lu
Guocai
G
D000110:Acetylcholinesterase / Q000097:blood; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002784:Cholesterol / Q000097:blood; D004285:Dogs; D005260:Female; D005755:Gastrins / Q000097:blood; D006403:Hematologic Tests; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D054328:Proton Pump Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D011725:Pyridines / Q000493:pharmacokinetics* / Q000633:toxicity*; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests; D014280:Triglycerides / Q000097:blood
D005755:Gastrins; D054328:Proton Pump Inhibitors; D011725:Pyridines; D014280:Triglycerides; C527452:pymeprazole; D002784:Cholesterol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000110:Acetylcholinesterase