chloramphenicol-succinate and Body-Weight

Non-metabolized polar antibiotics have a volume of distribution roughly equivalent to the extracellular fluid compartment and are cleared by the kidney. The volume of the ECF, therefore, affects the magnitude of Cmax when a constant dose is administered. Variations in glomerular filtration rate, or in the case of beta-lactams renal plasma flow, vary the rate at which the drug is cleared from the body. The pharmacokinetics of metabolizable antibiotics is complex; not only does prodrug pharmacokinetics affect the observed serum concentration of the active agent, but hepatic blood flow and biliary flow rate affect the rate at which such antibiotics (i.e., chloramphenicol) are removed from the serum. In these, general dosage guidelines are almost impossible in newborns; monitoring the serum concentrations is mandatory.

Topics: Aminoglycosides; Anti-Bacterial Agents; Body Weight; Chloramphenicol; Extracellular Space; Gentamicins; Glomerular Filtration Rate; Half-Life; Humans; Infant, Newborn; Kidney; Kinetics; Lactams; Liver; Liver Circulation; Metabolic Clearance Rate; Renal Circulation

Much toxicological research continues to be done using genetically undefined "outbred" stocks of mice and rats, although the case for using isogenic strains has been made repeatedly in the literature over a period of more than two decades. Also, very few studies are conducted using more than one strain, with the result that genetic variation in response is seldom apparent to the investigator. Here we report qualitative and quantitative strain differences in the haematological response to chloramphenicol succinate (CAPS) when administered by gavage at 500-2500 mg/kg for 7 days, to four inbred strains of mouse (C3H/He, CBA/Ca, BALB/c and C57BL/6) and one outbred stock (CD-1). CAPS caused anaemia and reticulocytopenia in all mouse strains, and leucopenia in the inbred strains but not in the outbred CD-1 stock. All four inbred strains showed significant (P<0.01) responses to CAPS at lower dose levels than in CD-1 mice, which were phenotypically more variable than the inbred animals. A simulated experiment, using a sample of records from the present study, showed that the use of two mice at each dose level using CD-1, CBA, BALB/c and C57BL/6 (48 total mice), would have given a more sensitive experiment than the use of 47 CD-1 mice alone, and would also have shown that the response is partly strain dependent. These studies provide additional evidence that inbred strains, because of their greater sensitivity and other valuable properties, should be more widely used in toxicology.

Topics: Analysis of Variance; Anemia, Aplastic; Animals; Blood Cells; Body Weight; Breeding; Chloramphenicol; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Genetic Variation; Genotype; Mice; Mice, Inbred Strains; Phenotype