Chloramphenicol pharmacokinetics

Studies of chloramphenicol pharmacokinetics were subsequently performed in newborns and children. High concentrations of chloramphenicol and its metabolites accumulated in newborns who developed toxicity (Figure 23.1 A)/ and presumably accounted for the severe toxicity. This accumulation of drug on a... 

Lugo Goytia G, Lares-Asseff I, Perez Guille MG, Perez AG, Mejia CL. Relationship between clinical and biologic variables and chloramphenicol pharmacokinetic parameters in pediatric patients with sepsis. Ann Pharmacother 2000 34(3) 393-7. 

Although there is limited evidence to surest that paracetamol may affect chloramphenicol pharmacokinetics its validity has been criticised. Evidence of a clinically relevant interaction appears to be lacking. 

Monitoring Monitoring serum levels is important because of the variability of chloramphenicol s pharmacokinetics. Monitor serum concentrations weekly monitor more often in patients with hepatic dysfunction, in therapy more than 2 weeks, or with potentially interacting drugs. 

Many antimicrobial agents have similar pharmacokinetic properties when given orally or parenterally (ie, tetracyclines, trimethoprim-sulfamethoxazole, quinolones, chloramphenicol, metronidazole, clindamycin, rifampin, linezolid and fluconazole). In most cases, oral therapy with these drugs is equally effective, is less costly, and results in fewer complications than parenteral therapy. 

In some cases, the same disease states exert no effect on drug pharmacokinetics as with amoxycillin and chloramphenicol in calves, and ampicillin and sulfamethazole in goats. Although feverish pigs show reduced elimination half-lives when oxytetracycline is given orally, there is no apparent effect after intravenous administration, which suggests an effect on gastrointestinal absorption (39). 

Apart from the pathophysiological condition of the animal, the mode of drug application may also significantly influence the pharmacokinetic profile of a drug (48, 49). For example, drug residues may persist at the injection site for prolonged periods of time (2). In a study in which various sulfonamides and trimethoprim were injected intramuscularly into swine, detectable residues were found at most sites 6 days after the injection, and with the sulfonamides at 30 days in almost half of the animals (50). Other drugs such as dihydrostreptomycin persist for up to 60 days, while positive residues of chloramphenicol are found at 7 days postinjection. Sodium and procaine penicillin, neomycin, tylosin, and oxytetracycline residues have also been determined at 24 h or more postinjection (51). 

Ambrose, P. J. 1984. Clinical pharmacokinetics of chloramphenicol and chloramphenicol sucGinate. Pharmacokin9 222-238. 

Burke, J. T., W. A. Virgin, R. J. Sherertz, K. L. Sanders, M. R. Blum, and F. A. Sarubbi. 1982. Pharmacokinetics of intravenous chloramphenicol sodium succinate in adult patients with normal renal and hepatic function. J. Pharmacokin. Biopharrrl0 601-614. 

Strebel, L., J. Miceli, R. Kauffman, R. Poland, A. Dajani, andA. Done. 1980. Pharmacokinetics of chloramphenicol (CAP) and chloramphenicol-succinate (CAP-Succ) in infants and chilflUem.Pharmacol. Ther. 27 288-289. 

Pharmacokinetics. For oral use, chloramphenicol is available as the base in capsules to reduce the bitter taste and for i.v. or i.m. use as the succinate ester which is soluble. Chloramphenicol succinate is... 

Paracetamol altered the pharmacokinetics of chloramphenicol in some studies but not in others. 

Kearns GL, Bocchini JA Jr, Brown RD, Cotter DL, Wilson JT. Absence of a pharmacokinetic interaction between chloramphenicol and acetaminophen in children. J Pediatr 1985 107(l) 134-9. 

Reiche, R., Mulling, M. Frey, H.-H. (1980) Pharmacokinetics of chloramphenicol in calves during the first weeks of life. Journal of Veterinary Pharmacology and Therapeutics, 3, 95-106. 

Antibiotics that require TDM include aminoglycosides, chloramphenicol, sulfonamides, vancomycin, trimethoprim, P-lactams, and tetracyclines. Pharmacokinetic details of these antibiotics are summarized in Table 33-4. Aminoglycosides and vancomycin are quantified by immmioassay. Other antibiotics have been measured by HPLC. 

Residues at the site of injection present specific problems. The persistence of residues at intramuscular injection sites may be due in part to the irritant response produced in the muscle. Chloramphenicol, tylosin, penicillins, dihydrostreptomycin and oxytetracycline have been shown to produce local irritation at the site of injection leading to residues persistence and this may be exacerbated by the solvent used (47-49) with one oxytetracycline product which produced little irritation, residues did not persist (49). Large variations in pharmacokinetic behaviour were noted in addition to the persistence at the injection site and in particular with oxytetracycline, bioavailability was reduced. These studies demonstrate the usefulness of pharmacokinetic data when studying specific routes of administration, and in particular they demonstrate the need to take into account other biological phenomena when attributing withdrawal periods, in this case, irritation at the injection site. The new draft EC Guideline requires that injection sites are examined in residues studies with injectable products and in the case of persistence at the site, then the withdrawal period will be based on this. 

Hepatic metabolism to the inactive glucuronide is the major route of elimination. This metabolite and chloramphenicol are excreted in the urine. Patients with impaired liver function have decreased metabolic clearance, and dose should be decreased. About 50% of chloramphenicol is bound to plasma proteins this is reduced in cirrhotic patients and in neonates. Half-life is not altered significantly by renal insufficiency or hemodialysis, and dose adjustment usually is not required. However, if the dose of chloramphenicol has been reduced because of cirrhosis, clearance by hemodialysis may be significant. Drug administration after hemodialysis minimizes this effect. Variabihty in the metabolism and pharmacokinetics of chloramphenicol in neonates, infants, and children necessitates monitoring of plasma drug levels. 

A. Classification and Pharmacokinetics Chloramphenicol has a simple and distinctive structure, and no other antimicrobials have been discovered in this chemical class. It is effective orally as well as parenterally and is distributed throughout all tissues it readily crosses the placental and blood-brain barriers. The dmg undergoes enterohepatic cycling, and a small fraction of the dose is excreted in the urine unchanged. Most of the drug is inactivated by a hepatic glu-curonosyltransferase. 

Different tissues have been shown to display different DNA pharmacokinetics. Genes and gene products have been observed as long as 19 months after direct injection without indication of plasmid integration or replication (175). Direct injection of the chloramphenicol acetyltransferase gene into the thyroid resulted in elimination of DNA from the gland with a half-life of 10 hours. The enzyme activity was maximal for 24 hours and eliminated through first-order kinetics with an apparent half-life of 40 hours (176). Similar results were recorded for synovial fluid intra-articular administration of plasmid DNA (177). 

Burrows GE, Barto PB, Martin B, Tripp ML, Comparative pharmacokinetics of antibiotics in newborn calves Chloramphenicol, lincomycin, and tylosin. Am. J. Vet. Res. 1983 44 1053-1057. 

Anadon A, Bringas P, Martinez-Larranaga MR, Diaz MJ, Bioavailability, pharmacokinetics and residues of chloramphenicol in the chicken, J. Vet. Pharmacol. Ther. 1994 17 52-58. 

Garg SK, Kumar B, Shukla VK, Bakaya V, Lai R, Kaur S. Pharmacokinetics of aspirin and chloramphenicol in normal and leprotic patients before and after dapsone therapy. IntJ Clin Pharmacol Ther Toxicol (1988) 26, 204-5. 

Dapsone does not significantly affect the pharmacokinetics of oral chloramphenicol... 

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