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Antipyrine as a Model Drug Substance to Assess Oxidative Metabolism

Antipyrine as a Model Drug Substance to Assess Oxidative Metabolism Abstract We read with interest the article by Crussell-Porter et al1 on the effect of low-dose fluconazole on the effect of warfarin. We agree with the conclusion of the authors that close monitoring of prothrombin times is recommended during concomitant therapy with fluconazole. Our division demonstrated a similar effect on the pharmacokinetics of terfenadine by fluconazole.2 We do, however, disagree with the authors' statement that the inhibitory effects of fluconazole are minimal because it does not alter the disposition of antipyrine in humans. While it is true that antipyrine has traditionally been considered a model drug for evaluating drug metabolizing capacity,3 hepatic oxidative metabolism involves numerous P450 subfamilies, all of which do not necessarily contribute to the metabolism of antipyrine.4 That is to say, antipyrine metabolism may be affected differently from warfarin5 or even unaffected by well-known inhibitors of drug metabolism,6 including ketoconazole.7,8 For References 1. Crussell-Porter LL, Rindone JP, Ford MA, Jaskar DW. Low-dose fluconazole potentiates the hypothrombinemic response of warfarin sodium . Arch Intern Med . 1993;153:102-104.Crossref 2. Honig PK, Wortham DC, Zamani K, et al. The effect of fluconazole on the steady-state pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine in humans . Clin Pharmacol Ther . 1993;53:630-636.Crossref 3. Poulsen HE, Loft S. Antipyrine as a model drug to study hepatic drug-metabolizing capacity . J Hepatol . 1988;6:374-382.Crossref 4. Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism . Crit Rev Toxicol . 1992;22:1-21.Crossref 5. Stenger C, Schlicht F, Walter E, et al. Effect of single and multiple doses of sulfinpyrazone on antipyrine metabolism and urinary excretion of 6-betahydroxycortisol . Eur J Clin Pharmacol . 1983;25:797-801.Crossref 6. Back DJ, Tjia J, Monig H, Ohnhaus EE, Park BK. Selective inhibition of drug oxidation after simultaneous administration of two probe drugs, antipyrine and tolbutamide . Eur J Clin Pharmacol . 1988;34:157-163.Crossref 7. Blyden GT, Abernethy DR, Greenblatt DJ. Ketoconazole does not impair antipyrine clearance in humans . Int J Clin Pharmacol Ther Toxicol . 1986; 24:205-206. 8. Daneshmend TK, Warnock DW, Ene MD, et al. Multiple dose pharmacokinetics of ketoconazole and their effects on antipyrine kinetics in man . J Antimicrob Chemother . 1983;12:185-188.Crossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Antipyrine as a Model Drug Substance to Assess Oxidative Metabolism

Antipyrine as a Model Drug Substance to Assess Oxidative Metabolism

Abstract

Abstract We read with interest the article by Crussell-Porter et al1 on the effect of low-dose fluconazole on the effect of warfarin. We agree with the conclusion of the authors that close monitoring of prothrombin times is recommended during concomitant therapy with fluconazole. Our division demonstrated a similar effect on the pharmacokinetics of terfenadine by fluconazole.2 We do, however, disagree with the authors' statement that the inhibitory effects of fluconazole are minimal...
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Publisher
American Medical Association
Copyright
Copyright © 1994 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinte.1994.00420050162015
Publisher site
See Article on Publisher Site

Abstract

Abstract We read with interest the article by Crussell-Porter et al1 on the effect of low-dose fluconazole on the effect of warfarin. We agree with the conclusion of the authors that close monitoring of prothrombin times is recommended during concomitant therapy with fluconazole. Our division demonstrated a similar effect on the pharmacokinetics of terfenadine by fluconazole.2 We do, however, disagree with the authors' statement that the inhibitory effects of fluconazole are minimal because it does not alter the disposition of antipyrine in humans. While it is true that antipyrine has traditionally been considered a model drug for evaluating drug metabolizing capacity,3 hepatic oxidative metabolism involves numerous P450 subfamilies, all of which do not necessarily contribute to the metabolism of antipyrine.4 That is to say, antipyrine metabolism may be affected differently from warfarin5 or even unaffected by well-known inhibitors of drug metabolism,6 including ketoconazole.7,8 For References 1. Crussell-Porter LL, Rindone JP, Ford MA, Jaskar DW. Low-dose fluconazole potentiates the hypothrombinemic response of warfarin sodium . Arch Intern Med . 1993;153:102-104.Crossref 2. Honig PK, Wortham DC, Zamani K, et al. The effect of fluconazole on the steady-state pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine in humans . Clin Pharmacol Ther . 1993;53:630-636.Crossref 3. Poulsen HE, Loft S. Antipyrine as a model drug to study hepatic drug-metabolizing capacity . J Hepatol . 1988;6:374-382.Crossref 4. Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism . Crit Rev Toxicol . 1992;22:1-21.Crossref 5. Stenger C, Schlicht F, Walter E, et al. Effect of single and multiple doses of sulfinpyrazone on antipyrine metabolism and urinary excretion of 6-betahydroxycortisol . Eur J Clin Pharmacol . 1983;25:797-801.Crossref 6. Back DJ, Tjia J, Monig H, Ohnhaus EE, Park BK. Selective inhibition of drug oxidation after simultaneous administration of two probe drugs, antipyrine and tolbutamide . Eur J Clin Pharmacol . 1988;34:157-163.Crossref 7. Blyden GT, Abernethy DR, Greenblatt DJ. Ketoconazole does not impair antipyrine clearance in humans . Int J Clin Pharmacol Ther Toxicol . 1986; 24:205-206. 8. Daneshmend TK, Warnock DW, Ene MD, et al. Multiple dose pharmacokinetics of ketoconazole and their effects on antipyrine kinetics in man . J Antimicrob Chemother . 1983;12:185-188.Crossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Mar 14, 1994

References