Studies on the chronic oral toxicity of an analgesic drug combination consisting of acetylsalicylic acid, paracetamol and caffeine in rats including an electron microscopical evaluation of kidneys.

The analgesic drug combination Thomapyrin consisting of acetylsalicylic acid (CAS 50-78-2, ASA), paracetamol (CAS 103-90-2, NAPAP) and caffeine (CAS 58-08-2) in the ratio 5:4:1 was investigated for its chronic toxicity in rats. For comparison the individual drugs ASA and NAPAP as well as the double combination ASA+NAPAP were tested in equipotent doses. 20 male and 20 female rats per group (Chbb:THOM/SPF) received doses of 50, 100 and 200 mg/kg of the combination ASA+NAPAP+caffeine, 45 and 180 mg/kg of the combination ASA+NAPAP, and 50 and 200 mg/kg of the individual drugs ASA or NAPAP over a period of 6 months. The daily dose was splitted into two parts and administered 3 h apart. The rats were single housed under standardized conditions with free access to food and drinking water. Plasma concentrations were measured in four additional animals of all high dose groups after the last dosing at seven time points. Besides the usual routine toxicological investigations the kidneys of five females per group were investigated by transmission electron microscopy. All investigations were performed according to GLP regulations. All animals behaved unobtrusively throughout the study with only minor impairment of general conditions in some animals of all ASA, ASA+NAPAP+caffeine and the high dose NAPAP groups. Dose related mortality was observed in the groups receiving ASA alone or in combination, partly with rales and tonic convulsions immediately prior to death. Body weight gain was decreased in males but not in females of the ASA+NAPAP+ caffeine and ASA groups. No consistent drug- and dose-dependent changes in hematological, clinico-chemical or urinanalytical parameters were observed, except for a slight increase in excretion of epithelial cells in both genders of the ASA groups. Plasma drug level monitoring demonstrated that the pharmacokinetics of ASA were not altered by co-administration of caffeine or NAPAP or vice versa. In males, maximum plasma concentrations (Cmax) and areas under the curve (AUC) for ASA and NAPAP tended to be slightly lower than in females. The plasma concentrations reached in the study represent a low multiple (2.2-7.9) of therapeutic plasma levels. Therefore, the results reported in the study can be considered representative for normal therapeutic use of the analgesic combination ASA+NAPAP+caffeine. Gastric erosions in the ASA and ASA+NAPAP+caffeine groups, increased kidney weights in females given 200 mg/kg ASA+NAPAP+caffeine, and dose-dependently increased liver weights in females given 200 mg/kg ASA and decreased liver weights in males at 100 and 200 mg/kg ASA-NAPAP+caffeine were the only consistent drug-induced changes observed at necropsy. Except for the above mentioned ulcer, all histopathological findings were iatrogenic or spontaneous lesions. The kidneys demonstrated initial stages of age-associated nephropathy at comparable incidence and severity in all groups including controls. Semi-thin section evaluation and transmission electron microscopy showed only minor changes. Taking all tubular and vascular changes together (total mean), the animals of the NAPAP group were slightly more affected than those of the other groups. Summing up it can be concluded that the nephrotoxic potential of the combination ASA+NAPAP+caffeine, if existing at all, was marginal even after prolonged administration, and that it does not exceed that of the monosubstances when given at pharmacologically equipotent doses and clinically relevant exposures.