Chloramphenicol metabolism

In order to validate the abstraction concept (Fig. 3.1), chloramphenicol was submitted as a PAC to biotransformation by S. cerevisiae. Chloramphenicol metabolism in man and rat has been fully elucidated [86, 87], yet its complexity necessitated simplification ... 

Phenobarbital can increase the rate of chloramphenicol metabolism and so lead to abnormally low serum chloramphenicol concentrations. In 17 children receiving chloramphenicol succinate alone, mean peak and trough serum concentrations were 25 and 13 pg/ml respectively. In six patients phenobarbital reduced these concentrations to 17 and 7.5 pg/ml respectively (76). 

Rifampicin can increase the rate of chloramphenicol metabolism and so lead to abnormally low serum chloramphenicol concentrations (79,80). 

Bella DD, Ferrari V, Marca G,Bonanomi L. Chloramphenicol metabolism in the phenobarbi-tal-inducedrat. Comparison with thiamphenicol. Biochem Pharmacol (1968) 17, 2381-90. 

It is important to monitor closely serum blood levels of chloramphenicol, particularly in patients with impaired liver or kidney function or when administering chloramphenicol with other drugs metabolized by the liver. Blood concentration levels exceeding 25 mcg/mL increase the risk of the patient developing bone marrow depression. 

Enterohepatic circulation can lead to toxic effects. For example, the drug chloramphenicol is metabolized to a conjugate that is excreted in bile by the rat. Once in the gut, the conjugate is broken down to release a phase 1 metabolite that undergoes further metabolism to yield toxic products. When these are reabsorbed, they can cause toxicity. The rabbit, by contrast, excretes chloramphenicol conjugates in urine, and there are no toxic effects at the dose rates in question. 

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. 

Several extraction techniques have also been described that use enzymatic or chemical reactions to improve extraction efficiency. A technique that has been used to increase the overall recovery of the marker residue is enzymatic hydrolysis to convert specific phase II metabolites (glucuronides or sulfates) back into the parent residue. Cooper etal used a glucuronidase to increase 10-fold the concentration of chloramphenicol residues in incurred tissue. As an example of a chemical reaction, Moghaddam et al. used Raney nickel to reduce thioether bonds between benomyl and polar cellular components, and as a result achieved a substantially improved recovery over conventional solvent extraction. In choosing to use either of these approaches, thorough characterization of the metabolism in the tissue sample must be available. 

Chloramphenicol Phenytoin, tolbutamide, ethanol Decreased metabolism of other agents Monitor phenytoin SDC, blood glucose... 

Ethanol increases phenobarbital metabolism, but valproic acid, cimeti-dine, and chloramphenicol inhibit its metabolism. 

The most important example to be discussed here is that of the drug chloramphenicol (11.39, R = 2-hydroxy-l-(hydroxymethyl)-2-(4-nitrophen-yl)ethyl, Fig. 11.7), the many metabolic pathways of which have yielded a wealth of information [75], The dichloroacetyl moiety is especially of interest in that dechlorination proceeds by three proven routes glutathione-dependent dechlorination, cytochrome P450 catalyzed oxidation, and hydrolysis. Of particular value is that the oxidative and hydrolytic routes can be unambiguously distinguished by at least one product, as shown in Fig. 11.7. Oxidation at the geminal H-atom produces an unstable (dichloro)hydroxyacet-amido intermediate that spontaneously eliminates HC1 to yield the oxamoyl... 

In conclusion, the oxamic acid derivative is produced by two distinct metabolic pathways, namely by oxidative and hydrolytic dechlorinations. In contrast, the primary alcohol metabolite 11.41 can be produced only by hydrolytic dechlorination and is, thus, an unambiguous marker of this pathway. The alcohol 11.41 is a known urinary metabolite of chloramphenicol in humans. 

Drugs must also be considered as foreign compounds, and an essential part of drug treatment is to understand how they are removed from the body after their work is completed. Glucuronide formation is the most important of so-called phase II metabolism reactions. Aspirin, paracetamol, morphine, and chloramphenicol are examples of drugs excreted as glucuronides. 

Sulthiame (H7, 04), phcnacoraidc (H15), chloramphenicol (C5),dicou-marol (H6), antituberculous drugs (K23), disulfiram and phenyramidol (S23) have been described as inhibitors of phenytoin metabolism, while alcohol and possibly phenobarbitone have the reverse effect. Clinical and experimental evidence regarding the latter are confusing (B16, B29, C11,C12). 

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. 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

Plasma phenytoin concentrations are increased in the presence of chloramphenicol, disulfiram, and isoniazid, since the latter drugs inhibit the hepatic metabolism of phenytoin. A reduction in phenytoin dose can alleviate the consequences of these drug-drug interactions. 

Age In newborn infants, the glomerular filtration rate and tubular transport is immature, which takes 5 to 7 months to mature. Also, the hepatic drug metabolism capacity is also inadequate (that is why chloramphenicol can produce grey baby syndrome ), and due to the higher permeability of blood brain barrier, certain drugs attain high concentration in the CNS. 

Chloramphenicol inhibits hepatic microsomal enzymes that metabolize several drugs. Half-lives are prolonged, and the serum concentrations of phenytoin, tolbutamide, chlorpropamide, and warfarin are increased. Like other bacteriostatic inhibitors of microbial protein synthesis, chloramphenicol can antagonize bactericidal drugs such as penicillins or aminoglycosides. 

Chloramphenicol [NE] Decreased dicumarol metabolism (probably also warfarin). 

Drugs that may inhibit cytochrome P450 metabolism of other drugs include amiodarone, androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin, clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydramine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, fluvoxamine, furanocoumarins (substances in grapefruit juice), indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, mexile-tine, miconazole, nefazodone, omeprazole, paroxetine, propoxyphene, quinidine, ritonavir, sulfamethizole, verapamil, voriconazole, zafirlukast, and zileuton. 

We have already discussed a therapeutic application of inhibition in the example of ethanol being used as an antidote to ethylene glycol or methanol poisoning. There are many other such cases which could also be cited. Antabuse , disulfiram, prevents the metabolism of ethanol. As a result a person under treatment with Antabuse will become violently ill if s/he consumes ethanol. Barbiturates are rapidly metabolized especially if a person has been on a prescription for some time. Administering the antibacterial chloramphenicol will inhibit the breakdown of barbiturates and in so doing prolong their sedative action. 

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. 

It is also of importance to recognize that just as small quantities of drugs can induce increased drug-metabolizing capacity, small amounts of some other drugs inhibit the rate of biotransformation. This delayed biotransformation can be seen within minutes after administration of drugs such as chloramphenicol (9). 

After infeed medication to swine, chloramphenicol was rapidly absorbed and declined rapidly thereafter due both to its rapid elimination and intensive metabolism (29). Chloramphenicol glucuronide was the main metabolite formed... 

The ability of liver to biotransform chloramphenicol has been also demonstrated in several fish species. In pertinent studies, various metabolic pathways were determined and chloramphenicol-glucuronide, chloramphenicol-base, chloramphenicol-alcohol, and chloramphenicol-oxamate were the main metabolites observed (34, 35). Following hepatic biotransformation, a large proportion of the administered dose was excreted in the urine. 

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