Chloramphenicol metabolic activation

Metabolism may be mediated by intestinal microflora, epithelial enzymes, or liver enzymes preceding entry into the systemic circulation. Chloramphenicol is well absorbed when administered orally to calves less than 1 week old, but it is inactivated by microflora when administered to ruminants. Similar observations have been made after oral administration of amoxicillin, ampicillin, and cephalexin therapy in young calves (11). On the other hand, trimethoprim, which is extensively metabolized in the liver and may undergo some metabolism in the rumen, shows higher systemic availability in the newborn calf and kid, due probably to the lower metabolic activity in the neonatal animal. 

Pohl, L. R., Nelson, S. D., Krishna, G. Investigation of the mechanism of the metabolic activation of chloramphenicol by rat liver micro-somes. Identification of a new metabolite. Biochem. Pharmacol. 1978, 27, 491-496. 

Strain. By these criteria, methyl methanesulfonate, A -acetoxyfluorenylacet-amide, captan, and others are preferential inhibitors of the pol Ai strain (Tables 7 and 8). On the other hand, streptomycin and chloramphenicol, although they induce lethality in both indicator strains, do not preferentially kill the pol Ar strain (SI = 1.12 and 1.02, respectively). It should be noted that this procedure is compatible with metabolic activation. Thus, the precarcinogens 2-aminofluorene and cyclophosphamide, which require metabolic activation by hepatic enzymes, do not preferentially inhibit the pol Ai strain in the absence of rat liver microsomes, but do so in the presence of this preparation (Tables 7 and 8). This procedure has the added advantage that results obtained by this modified pol Ai assay are expressed quantitatively, rather than as differences in the diameters of the zones of growth inhibition. As will be seen below, this modified procedure greatly increases the usefulness of the pol A assay (Table 9). 

Feedback inhibition of amino acid transporters by amino acids synthesized by the cells might be responsible for the well known fact that blocking protein synthesis by cycloheximide in Saccharomyces cerevisiae inhibits the uptake of most amino acids [56]. Indeed, under these conditions, endogenous amino acids continue to accumulate. This situation, which precludes studying amino acid transport in yeast in the presence of inhibitors of protein synthesis, is very different from that observed in bacteria, where amino acid uptake is commonly measured in the presence of chloramphenicol in order to isolate the uptake process from further metabolism of accumulated substances. In yeast, when nitrogen starvation rather than cycloheximide is used to block protein synthesis, this leads to very high uptake activity. This fact supports the feedback inhibition interpretation of the observed cycloheximide effect. 

Metabolism/Excretion -Toia urinary excretion of chloramphenicol ranges from 68% to 99% over 3 days. Most chloramphenicol detected in the blood is in the active free form. The elimination half-life of chloramphenicol is approximately 4 hours. 

Chloramphenicol and secobarbital exhibit properties similar to those of tienilic acid, but they have not been studied in humans (11). Oxidative dechlorination of chloramphenicol with formation of reactive acyl chlorides appears to be an important metabolic pathway for irreversible inhibition of CYP. Chloramphenicol binds to CYP, and subsequent substrate hydroxylation and product release are not impaired. The inhibition of CYP oxidation and the inhibition of endogenous NADPH oxidase activity suggest that some modification of the CYP has taken place, which inhibits its ability to accept electrons from the CYP reductase (11). Secobarbital completely inactivates rat CYP2B1 functionally, with partial loss of the heme chromophore. Isolation of the N-alkylated secobarbital heme adduct and the modified CYP2B1 protein revealed that the metabolite partitioned between heme N-alkylation, CYP2B1 protein modification, and epoxidation. A small fraction of the prosthetic heme modifies the protein and contributes to the CYP2B1 inactivation (12). 

An interaction of warfarin with ocular chloramphenicol (5 mg/ml 1 drop qds in each eye), which led to an increase in INR, has been suspected in an 83-year-old white woman (83). The authors suggested that the effect may be due to chloramphenicol inhibition of hepatic microsomal CYP2C9, since the pharmacologically active enantiomer 5-warfarin is metabolized by this enzyme). 

Chloramphenicol and florfenicol undergo hepatic metabolism (glucuronide conjugation) followed by active renal tubular secretion. Only 5-15% of the dose is excreted unchanged (glomerular filtration) in urine. The half-life of chloramphenicol and florfenicol are[Pg.34]

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