Evaluation of chronic oral toxicity and carcinogenic potential of lornoxicam in rats.
As part of the preclinical development program for lornoxicam, a novel non-steroidal anti-inflammatory drug (NSAID), its chronic oral toxicity and carcinogenic potential was assessed in Sprague-Dawley rats. Male and female rats were administered lornoxicam by oral gavage at 0, 0.06, 0.16 or 0.40 mg/kg/day for 12 months or at 0, 0.01 or 0.06 mg/kg/day in a supplementary low-dose study of the same duration (main group: 20/sex/group; 4-wk recovery: five/sex/group; satellites for electrocardiography and toxicokinetics: five/sex/group). Drug-related toxicity mainly comprised mortality, reduced body weight gain, clinico-pathological changes indicative of anaemia resulting from blood loss, and renal damage, renal papillary necrosis and gastrointestinal mucosal lesions. The kidney-associated changes were not completely reversible during the recovery period. Toxicokinetic investigations demonstrated a dose-linear absorption of the drug. In female rats the terminal half-life was about twice that in males which led to a higher exposure of this gender to lornoxicam. A dose of 0.01 mg/kg/day was established as no-observed-effect level. In a 104-wk carcinogenicity study, lornoxicam was administered by oral gavage to male and female rats (50/sex/group) at 0 (control 1), 0 (control 2), 0.0625, 0.125 or 0.250 mg/kg/day. In females only, the high dose was reduced twice during the study due to toxicity observed (0.250 to 0.200 to 0.160 mg/kg/day). Drug-related changes were similar to those in the chronic studies and consistent with the anticipated side-effects of NSAIDs. No carcinogenic potential was revealed.
Pohlmeyer-Esch
G
G
Nycomed Austria GmbH, Linz.
Mehdi
N
N
Clarke
D
D
Radhofer-Welte
S
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D010894:Piroxicam / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010894:Piroxicam; C059451:lornoxicam