ABSTRACT
Sprague-Dawley rats received daily oral gavage doses of either 2-retinylidene-5,5-dimethyl-1,3-cyclohexanedione (retinylidene dimedone; 14, 50, 150, or 330 mg/kg) or all-trans-retinoic acid (1, 4, 14, or 50 mg/kg) for 13 weeks. Rats given 50 mg/kg of all-trans-retinoic acid developed numerous long-bone fractures and became moribund during the third week of the study. Those receiving lower dosages survived until scheduled termination, but the 14 mg/kg group showed clear signs of retinoid intoxication including growth depression, anemia, serum alkaline phosphatase elevation, bone fracture, and testicular degeneration. Exposure to retinylidene dimedone did not result in any treatment-related deaths, growth depression, or histopathologic lesions, even at the highest dose, 300 mg/kg. Animals given this dosage exhibited mild anemia, equivocal evidence of bone fracture, but no increase in alkaline phosphatase activity. Retinylidene dimedone appears to be considerably less toxic than all-trans-retinoic acid.
Subject(s)
Retinoids/toxicity , Tretinoin/toxicity , Animals , Blood/drug effects , Body Weight/drug effects , Bone Diseases/chemically induced , Dose-Response Relationship, Drug , Female , Fractures, Bone/chemically induced , Male , Organ Size/drug effects , Rats , Rats, Inbred StrainsABSTRACT
Ingestible adsorbents for the removal of uremic metabolites are being investigated as adjunctive therapy in the treatment of chronic uremia. In particular, a microcapsule product containing urease and zirconium phosphate (UZP) has been investigated for removing urea. A dog model, simulating chronic uremia, was developed to investigate: (1) the concentration of various nitrogenous metabolites (urea, creatinine, and uric acid) in the GI tract, (2) flux rates of H2O and various nitrogenous metabolites in the GI tract, and (3) the efficacy of the microcapsule product. The results of these perfusion studies suggest that urea and creatinine can be removed from the GI tract via ingestible adsorbents. In addition, the model may be useful in investigating suspect uremic toxins, e.g., guanidinosuccinic acid (GSA). The reduction of blood urea nitrogen levels in the dog model when the animal was fed the microcapsule product was limited by the capacity of the zirconium phosphate to bind ammonium ion. Preliminary clinical studies with the microcapsule product indicate that it may be of potential adjunctive therapy in patients suffering from chronic renal failure.
Subject(s)
Capsules , Kidney Failure, Chronic/therapy , Urease/administration & dosage , Zirconium/administration & dosage , Administration, Oral , Adsorption , Animals , Creatinine/metabolism , Digestive System/metabolism , Dogs , Humans , Kidney Failure, Chronic/metabolism , Urea/metabolism , Uremia/therapy , Uric Acid/metabolismABSTRACT
1. Ftorafur, a fluorinated pyrimidine nucleoside antimetabolite, is metabolized by the beagle dog and rhesus monkey to 5-fluorouracil, which is subsequently biotransformed to the corresponding nucleosides, to alpha-fluoro-beta-ureidopropionic acid, to urea and to CO2. 2. In the dog, urea was the primary urinary metabolite while in the monkey, alpha-fluoro-beta-ureidopropionic acid predominated. 3. The dog and monkey excrete about 35 percent of the recovered dose as CO2. 4. The possibility that ftorafur is a relatively inactive transport form of 5-fluorouracil is discussed.
Subject(s)
Fluorouracil/analogs & derivatives , Tegafur/metabolism , Animals , Biotransformation , Dogs , Haplorhini , Macaca mulatta , Male , Tegafur/blood , Tegafur/urine , Time FactorsABSTRACT
The hepatic and renal microsomal drug metabolizing enzyme systems were isolated from homozygous nude Swiss (nu/nu), heterozygous normal Swiss (nu/+), homozygous normal Swiss (+/+) and DBA/2 mice. Microsomal protein and cytochrome P-450 concentrations were measured and the activity of ethylmorphine demethylase, aniline hydroxylase, aryl hydrocarbon hydroxylase and UDP-glucuronyl transferase were determined. Hepatic microsomes from both experimental groups carrying the nude gene were able to metabolize aniline and ethylmorphine more rapidly (20% and 36%, respectively) than the DBA/2 or Swiss homozygous normal mice. No difference between test groups was observed for hepatic aryl hydrocarbon hydroxylase or UDP-glucuronyl transferase activity. Kidney microsomes from mice carrying the nude gene had approximately twice the aryl hydrocarbon hydroxylase activity of the other two experimental groups. Renal mixed-function oxidase pathways measured for the homozygous nude mouse showed a higher overall rate of activity than the other three experimental groups. No significant difference in renal UDP-glucuronyl transferase was observed between mouse groups.
