cefpiramide and Body-Weight

From a search of the available literature, a database of 22 drugs of all charge types and several different therapeutic classes was compiled to compare rat and human biliary clearance data. Dog biliary excretion data were also found for nine of the drugs. For 19 of the 22 drugs (86%), rat unbound biliary clearance values, when normalized for body weight, exceeded those for humans by factors ranging from 9 to over 2500-fold, whereas human/dog differences were much less dramatic. It was possible to define hepatic uptake and efflux transporter involvement for many of the drugs. On the basis of the findings, it is postulated that regardless of the biliary efflux transporters implicated, when drugs do not require active hepatic uptake to access the liver there may be fairly insignificant differences in rat, dog, and human biliary clearance. Conversely, when the organic anion-transporting polypeptide drug transporters are involved, one may expect at least a 10-fold discrepancy in rat to human biliary clearance normalized for body weight and corrected for plasma protein binding.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Bile; Body Weight; Dogs; Drug Administration Routes; Humans; Liver; Membrane Transport Proteins; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Organic Anion Transporters; Pharmaceutical Preparations; Protein Binding; Rats; Species Specificity

A subchronic toxicity of cefpiramide (CPM) was studied in rhesus monkeys. The drug was administered intravenously to 4 groups of 2 males and 2 females each at a daily dose of 0, 100, 300 mg/kg and 1,000 mg/kg, respectively, for 6 weeks. Vomiting and diarrhea were observed at every dose of CPM, more frequently at the beginning of the treatment period. In addition, salivation was observed at 300 mg/kg or more and a transient subdued mood and inappetence at 1,000 mg/kg. A slight decrease of body weight was noted in a female given 1,000 mg/kg. There were no treatment-related changes in fecal occult blood test and electrocardiograms. Ophthalmological examinations showed no abnormalities being attributable to the treatment. A transient or slight anemia was observed in 2 monkeys receiving 1,000 mg/kg. Examination of bone marrow revealed no abnormalities. There were no effects on plasma biochemical parameters. In urinalysis, a female in the 1,000 mg/kg group showed a glycosuria. Kidneys of 3 animals given 1,000 mg/kg were pale at necropsy. Liver and kidneys were heavier in some animals at 300 mg/kg or more and at 1,000 mg/kg, respectively. Histological examination revealed a multifocal degeneration and regeneration of the proximal renal tubular epithelium in all animals receiving 1,000 mg/kg. No treatment-related changes were encountered in other organs and tissues. From these results, the maximum non-effective dose level of CPM was considered to be 300 mg/kg.

Topics: Animals; Blood; Body Weight; Bone Marrow Cells; Cephalosporins; Diarrhea; Eye; Female; Injections, Intravenous; Kidney; Liver; Macaca mulatta; Male; Organ Size; Vomiting

A chronic toxicity of cefpiramide (CPM) was studied in Cynomolgus monkeys. Groups of 4 males and 4 females were given daily doses of 100, 300 mg/kg or 600 mg/kg by intravenous administration for 26 weeks. Another group of 4 males and 4 females was given physiological saline and served as the control. In CPM groups, diarrhea or soft feces was observed after the commencement of administration at every doses. The frequency of these signs decreased as the study progressed and animals at lower doses returned to normal earlier. There were no treatment-related changes in body weights, fecal occult blood and electrocardiograms. A female in the 600 mg/kg group died after 13 weeks of treatment. The cause of death was assumed to be an acute myocardial necrosis resulting from thromboarteritis. It was not considered to be treatment-related. Ophthalmological examination revealed no abnormalities attributable to the treatment. Erythrocyte counts, hemoglobin and hematocrit values decreased in 3 animals receiving 600 mg/kg of the drug. The changes, however, were transient at least in 2 of these animals. There were no effects on plasma biochemical and urinalysis parameters. Small yellow spotes were noted in the renal cortex of 2 monkeys in the 600 mg/kg group at necropsy. Liver and kidneys were slightly heavier in animals receiving 600 mg/kg. Histopathological examinations revealed focal nonsuppurative interstitial nephritis in 1 animal given 300 mg/kg and 5 animals given 600 mg/kg. No treatment-related changes were observed in other organs and tissues. From these results, the maximum non-effective dose level of CPM was considered to be 100 mg/kg.

Topics: Animals; Blood; Body Weight; Cephalosporins; Eye; Female; Hematologic Tests; Injections, Intravenous; Kidney; Macaca fascicularis; Male; Organ Size