Chloramphenicol reduction

In pharmaceutical appHcations, the selectivity of sodium borohydride is ideally suited for conversion of high value iatermediates, such as steroids (qv), ia multistep syntheses. It is used ia the manufacture of a broad spectmm of products such as analgesics, antiarthritics, antibiotics (qv), prostaglandins (qv), and central nervous system suppressants. Typical examples of commercial aldehyde reductions are found ia the manufacture of vitamin A (29) (see Vitamins) and dihydrostreptomycia (30). An acyl azide is reduced ia the synthesis of the antibiotic chloramphenicol (31) and a carbon—carbon double bond is reduced ia an iatermediate ia the manufacture of the analgesic Talwia (32). 

Reduction chloramphenicol cinchonidine cinchonine nitrazepam physostigmine pyrithione quinidine quinine benzoxaprofen chlortetracycline demeclocycline dithranol menadione mercaptopurine methotrexate nalidixic acid oxolinic acid... 

In contrast to oxidative dechlorination, the hydrolytic dechlorination of chloramphenicol replaces a Cl-atom with a OH group to yield a (monochlo-ro)hydroxyacetamido intermediate. The latter, like the dichloro analogue, also eliminates HC1, but the product is an aldehyde that is far less reactive than the oxamoyl chloride intermediate. Chloramphenicol-aldehyde undergoes the usual biotransformation of aldehydes, namely reduction to the primary alcohol 11.41 and dehydrogenation to the oxamic acid derivative 11.40 (Fig. 11.7). 

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. 

The presence of multiple metabolites in the serum of neonates treated with chloramphenicol suggests that the biotransformation of chloramphenicol takes place by multiple routes to include oxidation, reduction, and conjugation. The presence of particular metabolites does not appear to correlate with toxicity. 

Nitro reductions RNOa -> RNO -> RNHOH -> RNH2 Nitrobenzene, chloramphenicol, clonazepam, dantrolene... 

Most of the drug is inactivated either by conjugation with glucuronic acid (principally in the liver) or by reduction to inactive aryl amines. Active chloramphenicol (about 10% of the total dose administered) and its inactive degradation products (about 90% of the total) are eliminated in the urine. A small amount of active drug is excreted into bile and feces. The systemic dosage of chloramphenicol need not be altered in renal insufficiency, but it must be reduced markedly in hepatic failure. Newborns less than a week old and premature infants also clear chloramphenicol less well, and the dosage should be reduced to 25 mg/kg/d. 

Several investigations on the stability of chloramphenicol during thermal treatment have been also carried out. Chloramphenicol has been found quite stable to heating when added to water or milk. Even after 2 hours of boiling, no more than 8% loss of its amount could be observed by physicochemical methods of analysis (16). Application of microbiological methods has shown, however, a 33.3-35% reduction in the activity of chloramphenicol after heating the milk or water samples at 100 C for 30 min (3). 

To remove lipids, sample extracts are frequently also partitioned with n-hexane (25, 33-35, 37, 40, 43, 45, 47, 49, 50, 53-57, 62), petroleum ether (31, 38, 63), isooctane (36, 41, 48), or toluene (26, 58, 59, 61). Use of n-toluene is not recommended, however, in chloramphenicol and florfenicol analysis, because these drugs have the tendency to transfer into toluene to some extent during the partitioning process. As an alternative to the classic liquid-liquid partitioning cleanup, some workers in the field (24, 26, 34, 58, 59) have suggested use of diatomaceous earth columns as another option of a liquid-liquid partitioning process that offers substantial reduction in emulsification problems and, thus, allows a high recovery increase. 

Metabolism is almost always an oxidative process. Reductive metabolism is much more limited. Functional groups that are reduced are, naturally, in a higher oxidation state. The more common examples include nitro groups, which are reduced to amines, and ketones, which reduce to alcohols. Chloramphenicol (8.28), an antibiotic that has fallen out of favor because of serious side effects, contains a nitro group that is reduced to the corresponding amine (8.29) (Scheme 8.9).7 Warfarin (Coumadin, 8.30), an anticlotting agent, is at least partially metabolized by reduction of its ketone to an alcohol. 

Operation of amperometric detectors in the reductive mode is more difficult because dissolved oxygen in the sample and mobile phase will interfere. Nevertheless, the quinone of doxorubicin and the nitro group of chloramphenicol have been reduced [94]. 

Fig. 3.7 Carboligation of bis-dechloro chloramphenicol (17). The doubly activated a-carboxylic position (arrow) reacts readily with acetaldehyde to give carbinols 18 and 20, respectively. The adducts react further by dehydration followed by reduction.

Whether or not a chloramphenicol stereoisomer is formed needs to be determined by investigating biochemical reduction of dehydrochloramphenicol. 

Aldehyde reduction Azo reduction Nitro reduction RCHO RCHjOH R,N = NR2 R,NH2 + R2NH2 o2nr H2NR Chloral hydrate Azo gantrisin Chloramphenicol... 

A reduction in particle size results in an increase in the surface area, which facilitates an increase in the dissolution rate and therefore, also, an increase in the rate of absorption. Drugs administered as suspension are generally rapidly absorbed because of the large available surface area of the dispersed solid. For solid dosage forms such as tablets and capsules, decreasing the particle size facilitates dissolution and thus absorption. Figure 6.8 shows the effect of particle size on absorption and resultant blood levels after oral administration of chloramphenicol in rabbits. Peak blood levels occurred much faster with the smaller... 

A reaction in which the oxidized or reduced form of a compound isomerizes via a first-order process on the voltammetric time-scale is common for a wide range of organometallic and organic compounds (for example Bard etal., 1973 Bond et al., 1986,1988,1992). An example from the field of organic chemistry involves the reduction of diethyl maleate to its radical anion which then isomerizes to the diethyl fumarate anion, again an overall EC mechanism (Bard et al., 1973). There is a wide range of examples of other EC mechanisms such as the reduction of the antibiotic chloramphenicol in which a nitro unit (-NO2) is reduced to a hydroxylamine (-NHOH) (E step) which rapidly converts into a nitroso (-NO) species (C step) (Kissinger and Heineman, 1983). 

Electrochemical detectors can be used in the oxidative mode for a wide range of drugs, including cannabinoids, haloperidol, morphine, paracetamol, phenothiazines, salicylic acid, and tricyclic antidepressants. Operation in the reductive mode is more difficult as dissolved oxygen must be removed from the eluent (K. Bratin et al, J. liq. Chromat., 1981,, 1777-1795). Reductive applications include chloramphenicol and benzodiazepines. 

Enzymatic Inactivation (e.g.. Hydrolysis) Covalent Modification Oxidation/Reduction P-Lactams, Fosfomycin Aminoglycosides, Chloramphenicol Tetracycline... 

Much of Landsteiner s pioneer work was carried out with haptens that were aromatic amines. The compounds were converted to diazonium salts with nitrous acid and aUowed to react with proteins at alkaline pH (approximately 9). Reaction occurred primarily with histidine, tyrosine, and tryptophan residues of the protein carrier. For a representative procedure, see Kabat (p. 799 seq.). An interesting application of this procedure was the preparation of a chloramphenicol-protein conjugate which was used to elicit antibodies specific for chloramphenicol. In this case, a prior reduction of the nitro group of chloramphenicol to an amino group was required. As early as 1937, carcinogenic compounds were conjugated to protein carriers by means of their isocyanate derivatives which were prepared from amines. Immune sera were raised, and their properties were studied. - ... 

Inhibition of tacrolimus clearance has been observed in an adolescent renal transplant recipient who was treated with standard doses of chloramphenicol for vancomycin-resistant enterococci. Toxic concentrations of tacrolimus were observed on the second day of chloramphenicol treatment, requiring an 83% reduction in the dose of tacrolimus (81). 

Bacterial reductase present in the intestine also tends to complicate in vivo interpretations of nitro reduction. For example, in rats, the antibiotic chloramphenicol is not reduced in vivo hy the liver but is excreted in the bile and, subsequently, reduced by intestinal flora to form the amino metabolite." ... 

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