Evaluation of chronic oral toxicity and carcinogenic potential of lornoxicam in rats

• Published in: Food and chemical toxicology 1997-09, Vol.35 (9), p.909-922
• Main Authors: Pohlmeyer-Esch, G., Mehdi, N., Clarke, D., Radhofer-Welte, S.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - toxicity; Biological and medical sciences; Dose-Response Relationship, Drug; Drug toxicity and drugs side effects treatment; Female; Kidney - drug effects; Kidney - pathology; Male; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Neoplasms, Experimental - chemically induced; Pharmacology. Drug treatments; Piroxicam - analogs & derivatives; Piroxicam - pharmacokinetics; Piroxicam - toxicity; Rats; Rats, Sprague-Dawley; Sex Factors
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/S0278-6915(97)00062-8

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.