Chloramphenicol prodrug

Benzoic acids substituted with a basic side chain also are also of interest as pro-moieties whose physicochemical properties and rates of enzymatic hydrolysis can readily be modulated. A number of drugs have been converted to prodrugs with this type of pro-moiety, e.g., hydrocortisone, prednisolone, acyclovir, chloramphenicol, and paracetamol [148] [149], These prodrugs appear well suited as parenteral formulations, being water-soluble, stable in slightly acidic solution, and readily hydrolyzed enzymatically. As examples, we consider here the hydrolysis in human plasma of a number of (aminomethyl)ben-zoates of metronidazole (8.109-8.115, Sect. 8.5.5.1, Table 8.9) [138], These prodrugs are very rapidly activated, which may be beneficial for parenteral administration. However, this type of pro-moiety may be cleaved too rapidly after oral administration to be of interest for poorly absorbed drugs. 

E. Jensen, H. Bundgaard, Aminomethylbenzoate Esters of Chloramphenicol as a Novel Prodrug Type for Parenteral Administration , Int. J. Pharm. 1991, 70, 137- 146. 

Absorption - Chloramphenicol base is absorbed rapidly from the intestinal tract and is 75% to 90% bioavailable. The inactive prodrug, chloramphenicol palmitate, is rapidly hydrolyzed to active chloramphenicol base. Bioavailability is approximately 80% for the palmitate ester. The bioavailability of the IV... 

The usual dosage of chloramphenicol is 50-100 mg/kg/d. After oral administration, crystalline chloramphenicol is rapidly and completely absorbed. A 1-g oral dose produces blood levels between 10 and 15 mcg/mL. Chloramphenicol palmitate is a prodrug that is hydrolyzed in the intestine to yield free chloramphenicol. The parenteral formulation is a prodrug, chloramphenicol succinate, which hydrolyzes to yield free chloramphenicol, giving blood levels somewhat lower than those achieved with orally administered drug. Chloramphenicol is widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid, such that the concentration of chloramphenicol in brain tissue may be equal to that in serum. The drug penetrates cell membranes readily. 

In recent years, many parent drugs have been converted to esters to generate so-called prodrugs in order to overcome some undesirable property such as bitter taste, poor absorption, poor solubility, and irritation at site of injection. For example, antibiotics such as chloramphenicol [56-75-7] and clindamycin [18323-44-9] have been derivatized as their palmitate esters in order to minimize their bitter taste. 

Prodrugs can be used to increase or decrease the aqueous solubility, mask bitterness, increase lipophili-city, improve absorption, decrease local side effects, and alter membrane permeability of the parent molecule. For example, chloramphenicol has an aqueous solubility of 2.5mg/ml, but chloramphenicol sodium succinate, a prodrug, has an aqueous solubility of lOOmg/ml. Hydantoins also possess low aqueous solu-bilites that result in low and variable availability and precipitation following injection. In an effort to increase the aqueous solubility of phenytoin, Stella et prepared the ethyl and triethylamine esters... 

Pancreatic enzyme activity may be low at birth, but enzymes such as amylase, lipase, and trypsin develop to adult levels within the first year of life. Premature infants appear to have lower amylase levels than do full-term infants. Low concentrations of pancreatic enzymes may be the reason why newborns have a decreased ability to cleave prodrug esters such as chloramphenicol palmitate. Lipid-soluble drugs may not be well absorbed by neonates because of low lipase concentrations and bile acid pool. ... 

Chloramphenicol Palmitate, USP. Chloramphenicol palmitate is the palmitic acid ester of ehloramphenieol. It is a tasteless prodrug of chloramphenicol intended for pcdiatric usc. The ester must hydrolyze in vivo following oral absorption to provide the active form. Erratic scrum levels were asstK iated with early formulations of the palmitatc. but the manufacturer claims that the bioavailability of the current preparation is comparable to that of ehloramphenieol itself. 

Procedures for the determination of chloramphenicol concentrations in blood serum include HPLC and immunoassay. Methods for chloramphenicol determination must be able to differentiate between the prodrug forms, chloramphenicol palmitate or succinate, and their active metabolite, chloramphenicol. (An HPLC method for measuring chloramphenicol is included on this book s accompanying Evolve site, found at http //evoIve. elsevier.com/Tietz/textbook/.)... 

Oral drugs with a markedly bitter taste may lead to poor patient compliance if administered as a solution or syrup. The prodrug approach has been used to improve the taste of chloramphenicol (20), clindamycin, erythromycin, and metronidazole.19 A prodrug such as chloramphenicol palmitate (21), with LogP of around 10, does not dissolve in an appreciable amount in the mouth and, therefore, does not interact with the taste receptors. 

On the other hand, formation of a prodrug such as a phosphate ester may increase hydrophilicity, thus enhancing solubility. For example, the solubility and dissolution rate of the 77-hydroxymethyl derivative of lomefloxacin is higher than those of the parent compound, and it can be converted readily back to the original molecule. Commonly used prodrugs are procaine penicillin metronidazole phosphate and chloramphenicol sodium succinate. 

CHLORO- mycehn) Is absorbed rapidly from the GI tract. For intravenous or intramuscular use, chloramphenicol succinate is a prodrug that is hydrolyzed by esterases to chloramphenicol in vivo. Chloramphenicol succinate is rapidly cleared from plasma by the kidneys this may reduce bioavaB-ability, since up to 30% of the dose may be excreted before hydrolysis. Poor renal fimction in the neonate and other states of renal insufficiency result in increased plasma concentrations of chloramphenicol succinate. Decreased esterase activity has been observed in the plasma of neonates and infants, prolonging time to peak concentrations of active chloramphenicol (up to 4 hours) and extending the period over which renal clearance of chloramphenicol succinate can occur. 

Reduction. Reduction, for example azo- and nitro-reduc-tion, is a less common pathway of drug metabolism. Reductase activity is found in the microsomal fraction and in the cytosol of the hepatocyte. Anaerobic intestinal bacteria in the lower gastrointestinal tract are also rich in these reductive enzymes. A historical example concerns Prontosil, a sulfonamide prodrug. It is metabolized by azo-reduction to form the active metabolite, sulfanilamide. Sulfasalazine is also cleaved by azoreduction by intestinal bacteria to form aminosalicylate, the active component, and sulfapyridine. Chloramphenicol is metabolized by... 

Note. The "prodrug" of chloramphenicol viz., chloramphenicol palmitate (USP), which is a tasteless product, is solely intended for pediatric nsage profnsely, because the parent drug has a distinct bitter taste. 

Ester prodrugs are used for a variety of reasons, not just for increasing the rate of absorption for a drug. For example, consider the structure of the antibiotic agent chloramphenicol ... 

Expert system, softdrug, prodrug, metabolism, computer system, chloramphenicol. 

Chloramphenicol sodium succinate Figure 8.24 Chloramphenicol ester prodrugs. 

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