Abstract
The induction of hepatic microsomal enzymes leading to more rapid metabolism of antibiotics has been demonstrated in only a few prior studies. We have studied the induction of chloramphenicol metabolism in an isolated rat liver perfusion model and in intact dogs. Using these methods, we have demonstrated that the clearance of chloramphenicol from serum is markedly increased after treatment of animals with phenobarbital. This was demonstrated to be a function of increased clearance of the drug by the liver, accompanied but not paralleled by increases in liver weight and biliary excretion by the rat liver. In intact dogs, small doses of chloramphenicol were not sufficient to demonstrate this fact, whereas a large test dose of 100 mg/kg showed markedly enhanced clearance after 1 week of oral phenobarbital administration. Prolongation of phenobarbital treatment or increased dose did not further increase the clearance, and chloramphenicol could not be demonstrated to enhance its own clearance. Human data on induction of enzymes is to date inconclusive.
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Selected References
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- BRODIE B. B., GILLETTE J. R., LA DU B. N. Enzymatic metabolism of drugs and other foreign compounds. Annu Rev Biochem. 1958;27(3):427–454. doi: 10.1146/annurev.bi.27.070158.002235. [DOI] [PubMed] [Google Scholar]
- BURNS J. J. IMPLICATIONS ON ENZYME INDUCTION FOR DRUG THERAPY. Am J Med. 1964 Sep;37:327–331. doi: 10.1016/0002-9343(64)90190-1. [DOI] [PubMed] [Google Scholar]
- Christensen L. K., Skovsted L. Inhibition of drug metabolism by chloramphenicol. Lancet. 1969 Dec 27;2(7635):1397–1399. doi: 10.1016/s0140-6736(69)90937-4. [DOI] [PubMed] [Google Scholar]
- Conney A. H. Pharmacological implications of microsomal enzyme induction. Pharmacol Rev. 1967 Sep;19(3):317–366. [PubMed] [Google Scholar]
- Despopoulos A. Congruence of excretory functions in liver and kidney: hippurates. Am J Physiol. 1966 Apr;210(4):760–764. doi: 10.1152/ajplegacy.1966.210.4.760. [DOI] [PubMed] [Google Scholar]
- FOUTS J. R., BRODIE B. B. The enzymatic reduction of chloramphenicol, p-nitrobenzoic acid and other aromatic nitro compounds in mammals. J Pharmacol Exp Ther. 1957 Feb;119(2):197–207. [PubMed] [Google Scholar]
- Govier W. C. Reticuloendothelial cells as the site of sulfanilamide acetylation in the rabbit. J Pharmacol Exp Ther. 1965 Nov;150(2):305–308. [PubMed] [Google Scholar]
- HUGHES D. W., DIAMOND L. K. CHLORAMPHENICOL IN BLOOD: SIMPLE CHEMICAL ESTIMATIONS IN PATIENTS RECEIVING MULTIPLE ANTIBIOTICS. Science. 1964 Apr 17;144(3616):296–297. doi: 10.1126/science.144.3616.296. [DOI] [PubMed] [Google Scholar]
- KAKEMI K., OHASHI S. [Chemical method for the determination of antibiotics. XV. Colorimetric determination of chloramphenicol]. Yakugaku Zasshi. 1962 Mar;82:338–342. doi: 10.1248/yakushi1947.82.3_338. [DOI] [PubMed] [Google Scholar]
- Klaassen C. D. Effects of phenobarbital on the plasma disappearance and biliary excretion of drugs in rats. J Pharmacol Exp Ther. 1970 Nov;175(2):289–300. [PubMed] [Google Scholar]
- REMMER H., MERKER H. J. EFFECT OF DRUGS ON THE FORMATION OF SMOOTH ENDOPLASMIC RETICULUM AND DRUG-METABOLIZING ENZYMES. Ann N Y Acad Sci. 1965 Mar 12;123:79–97. doi: 10.1111/j.1749-6632.1965.tb12247.x. [DOI] [PubMed] [Google Scholar]
- Riegelman S., Rowland M., Epstein W. L. Griseofulvin-phenobarbital interaction in man. JAMA. 1970 Jul 20;213(3):426–431. [PubMed] [Google Scholar]
- Tobon F., Mezey E. Effect of ethanol administration on hepatic ethanol and drug-metabolizing enzymes and on rates of ethanol degradation. J Lab Clin Med. 1971 Jan;77(1):110–121. [PubMed] [Google Scholar]
- Wooles W. R., Munson A. E. The effect of stimulants and depressants of reticuloendothelial activity on drug metabolism. J Reticuloendothel Soc. 1971 Feb;9(2):108–119. [PubMed] [Google Scholar]