Dose-response relationship of dexrazoxane for prevention of doxorubicin-induced cardiotoxicity in mice, rats, and dogs.

Dexrazoxane [(DZR), ADR 529, ICRF-187] ameliorates doxorubicin (DOX)-induced cardiotoxicity in animals, and is recommended as a cardioprotectant in patients receiving cumulative doses of DOX above 300 mg/m2. A DZR:DOX dose ratio of 10:1 is recommended based on studies in patients receiving 50 mg/m2. Since DOX may be used at much higher doses in certain clinical settings, we evaluated the ability of DZR to protect against cardiomyopathy in animals given bolus doses of DOX at varying dose levels. The severity and extent of the cardiomyopathy were evaluated histologically and expressed as the mean total score (MTS). Mice were given 10 doses of DOX (2 or 4 mg/kg) over a 7-week period. Without DZR, the MTS 4 weeks after the last treatment was 3.7 with 4 mg/kg DOX and 1.3 with 2 mg/kg DOX. DZR at 5:1, 10:1, and 20:1 dose ratios caused a dose-dependent decrease in the MTS but was less efficacious with the higher, more cardiotoxic dose of DOX. Rats were given DOX at 0.2, 0.4, and 0.8 mg/kg with a 20:1 ratio of DZR weekly for 13 weeks. Cardiomyopathy was most severe with the highest dose of DOX in the absence of DZR, especially in males, and progressed during the 6 weeks following the last treatment. DZR reduced the MTS in both sexes but in the males given the highest dose of DOX, there was still a significant amount of cardiac damage compared to vehicle-treated controls. Dogs were given 0.1, 0.3, and 0.8 mg/kg DOX with 20:1 DZR for 13 weeks. DZR reduced the MTS significantly (P < 0.05) in males and females but cardiac lesions were still present in each of the DZR-treated dogs. The results indicate that although DZR is highly effective in attenuating the cardiomyopathy caused by DOX, dose ratios of DZR:DOX capable of providing total or nearly complete cardioprotection at low doses of DOX are less efficacious at higher doses of DOX. One possible explanation for this effect is the marked pharmacokinetic difference between DZR and DOX, with DZR undergoing a much more rapid rate of elimination from the body compared to DOX. These findings point to the need for further studies to optimize the dose scheduling of DZR before using it clinically with bolus doses of DOX above those currently recommended.

The effects of cholestyramine, colestipol, and ADR-132 on the rat prostate and dunning R-3327 adenocarcinoma.

The effects of three compounds known to have hypocholesterolemic activity in several species were investigated on the rat prostate and the hormone-dependent R-3327 rat prostatic adenocarcinoma. Cholestyramine, colestipol, and ADR-132 are bile acid-sequestering anion exchange resins which were fed to separate groups of adult male Copenhagen X Fischer (F1) hybrid rats in doses of 0.25%, 1.00%, and 2.00% of diet. The results indicate that serum cholesterol levels in tumor-bearing rats and controls fed these compounds for 29 days were not reduced. The body and organ weights as well as the histological features of the prostate gland, seminal vesicles, and the R-3327 tumor were unaffected by these agents.

Bioavailability of sulpiride tablet and capsule in dogs.

The in vitro dissolution rates from four tablet formulations and one capsule formulation were measured in simulated gastric and simulated intestinal fluids. The dissolution t50% in simulated gastric fluid ranged from 1.5 min to 30 min and in simulated intestinal fluid, the values ranged from 4 to 228 min. The relative rates and rank order between products with regard to their dissolution rate were maintained. No correlation was obtained between in vitro dissolution rate and overall bioavailability in dogs as measured by the amounts of unchanged sulpiride excreted in the urine. The total unchanged sulpiride excreted in the 48 hr urine ranged from 30 to 44 % of the dose. The urinary half-lives ranged from 3.9 to 4.9 hr. The results indicate that, in the case of sulpiride, in vitro dissolution rate may not be a good predictor of bioavailability.

Bioavailability of 14C-sulpiride in dogs.

The plasma and urinary concentrations of unchanged 14C-sulpiride were measured in the dog following i.v. and oral administration. Bioavailability of the oral hydrochloride solution was 85% and that of the free base suspension was 75%. Sulpiride equilibrated rapidly with tissue fluid and had an apparent volume of distribution of 3.3--3.8 1/kg. The plasma half-life was 2.5--3 hours. The short plasma half-life and its negligible concentrations in the brain are consistent with the low lipophilicity of supliride. When 100 mg sulpiride was given orally either as hydrochloride or free base, the maximum plasma level was reached within one hour and concentrations were 2.3 and 1.8 micrograms/ml, respectively. The similarity of urinary excretion data from i.v. and oral preparations suggest minimal "first-pass" effect.

Inhibition of saline-induced diuresis in the rat by sulpiride.

Sulpiride (120 mg/kg, i.p.) inhibited saline-induced diuresis in the rat, an effect not observed with haloperidol, clozapine, pimozide or chloromazine. The antidiuretic effect of sulpiride also occurred in hypophysectomized rats suggesting that the response was not prolactin-mediated.

Metabolism of sulpiride in man and rhesus monkeys.

The metabolism of 14C-carbonyl-sulpiride (form A) and of 14C-3, 4 pyrrolidine-sulpiride (form B) was studied in the rhesus monkey and man. In the monkey, the metabolites in both the urine and the bile were the same with form A and form B: 60-80% sulpiride, 10-30% 5-oxopyrrolidine sulpiride and 3-8% an unidentified metabolite (ME-X). In four human volunteers given a single oral dose of either 108 mg form A or 100 mg form B, more than 95% of the 14C recovered in the urine and feces was unchanged sulpiride. Sulpiride levels in plasma reached maximum in 3 hr and ranged from 232 to 403 ng/ml. The plasma t1/2 was 8.3 hr. Pharmacokinetic analyses indicated little or no biliary excretion of sulpiride in man.