STUDIES ON THE CHRONIC ORAL TOXICITY OF AN ANALGESIC DRUG-COMBINATIONCONSISTING OF ACETYLSALICYLIC-ACID, PARACETAMOL AND CAFFEINE IN RATS INCLUDING AN ELECTRON-MICROSCOPIC EVALUATION OF KIDNEYS

The analgesic drug combination Thomapyrin(R) consisting of acetylsalic ylic acid (CAS 50-78-2, ASA), paracetamol (CAS 103-90-2, NAPAP) and ca ffeine (CAS 58-08-2) in the ratio 5:4:1 was investigated for its chron ic toxicity in rats. For comparison the individual drugs ASA and NAPAP as well as the double combination ASA + NAPAP were tested in equipote nt doses. 20 male and 20 female rats per group (Chbb:THOM/SPF) receive d doses of 50, 100 and 200 mg/kg of the combination ASA + NAPAP +caffe ine, 45 and 180 mg/kg of the combination ASA + NAPAP, and 50 and 200 m g/kg of the individual drugs ASA or NAPAP over a period of 6 months. T he daily dose was splitted into two parts and administered 3 h apart. The rats were single housed under standardized conditions with free ac cess to food and drinking water. Plasma concentrations were measured i n four additional animals of all high dose groups after the last dosin g at seven time points. Besides the usual routine toxicological invest igations the kidneys of five females per group were Investigated by tr ansmission electron microscopy. All investigations were performed acco rding to GLP regulations. All animals behaved unobtrusively throughout the study with only minor impairment of general conditions in some an imals of all ASA, ASA + NAPAP + caffeine and the high dose NAPAP group s. Dose related mortality was observed in the groups receiving ASA alo ne or in combination, partly with rales and tonic convulsions immediat ely prior to death. Body weight gain was decreased in males but not in females of the ASA + NAPAP + caffeine and ASA groups. No consistent d rug- 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. Pl asma drug level monitoring demonstrated that the pharmacokinetics of A SA were not altered by coadministration of caffeine or NAPAP or vice v ersa. In males, maximum plasma concentrations (C-max) 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 lo w multiple (2.2-7.9) of therapeutic plasma levels. Therefore, the resu lts reported in the study can be considered representative for normal therapeutic use of the analgesic combination ASA + NAPAP + caffeine. G astric erosions in the ASA and ASA + NAPAP + caffeine groups, increase d kidney weights in females given 200 mg/kg ASA + NAPAP +caffeine, and dose-dependently increased liver weights in females given 200 mg/kg A SA 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 demonstra ted initial stages of age-associated nephropathy at comparable inciden ce and severity in all groups including controls. Semithin section eva luation and transmission electron microscopy showed only minor changes . Taking all tubular and vascular changes together (total mean), the a nimals of the NAPAP group were slightly more affected than those of th e other groups. Summing up it can be concluded that the nephrotoxic po tential of the combination ASA + NAPAP + caffeine, if existing at all, was marginal even after prolonged administration, and that it does no t exceed that of the monosubstances when given at pharmacologically eq uipotent doses and clinically relevant exposures.