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.
Center of Evaluation for Drug Safety, Second Military Medical University, Shanghai 200433, China.
Yu
Y
Mao
Xiaodong
X
Zhang
Li
L
Li
Bojun
B
Yuan
Guocai
G
Lu
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