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. 1988 Oct;26(4):373–384. doi: 10.1111/j.1365-2125.1988.tb03394.x

Relationship between the metabolism of antipyrine, hexobarbitone and theophylline in man as assessed by a 'cocktail' approach.

J H Schellens 1, J H van der Wart 1, M Danhof 1, E A van der Velde 1, D D Breimer 1
PMCID: PMC1386557  PMID: 3190987

Abstract

1. Three model substrates for the characterization of drug oxidation activity, antipyrine (AP), hexobarbitone (HB) and theophylline (TH), were administered to 26 healthy volunteers on two different occasions: in the first experiment a combination of AP (250 mg) and HB (250 mg) was given and in the second experiment TH (150 mg) was added to the former combination. 2. Plasma concentrations of AP, HB and TH and urinary excretion of TH and the three main metabolites of AP (3-hydroxymethylantipyrine: HMA, norantipyrine: NORA and 4-hydroxyantipyrine: OHA) were determined and the intrinsic clearance (CLint) of the three substrates and the clearance to the formation of AP metabolites were calculated. 3. The correlation coefficients between CLHB and CL-greater than metabolites of AP were highest for CL-greater than HMA and CL-greater than NORA (greater than 0.80) and lowest for CL-greater than OHA (0.63). High correlation coefficients also were found between CLTH and CL-greater than OHA (0.89) and CL-greater than HMA (0.80). 4. Ideal relationships, defined by a slope of the orthogonal regression line equal to unity, did exist between CLHB and CL-greater than HMA as well as CL-greater than NORA and between CLTH and CLAP as well as CL-greater than OHA. 5. Based on the results of correlation and regression analysis it can be concluded that isozymes of the cytochrome P-450 system responsible for the oxidation of HB and formation of HMA and NORA are very closely related and also that isozymes responsible for the oxidation of TH and formation of OHA show a very close relation. 6. With this strategy of simultaneous administration of substrates ('cocktail' approach) it seems possible to characterize and correlate activities of different P-450 isozymes and to investigate their in vivo substrate selectivity without the disturbing influence of intra-individual variation in drug oxidation.

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Selected References

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  1. Birkett D. J., Miners J. O., Attwood J. Evidence for a dual action of sulphinpyrazone on drug metabolism in man: theophylline-sulphinpyrazone interaction. Br J Clin Pharmacol. 1983 May;15(5):567–569. doi: 10.1111/j.1365-2125.1983.tb02093.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boobis A. R., Brodie M. J., Kahn G. C., Toverud E. L., Blair I. A., Murray S., Davies D. S. Comparison of the in vivo and in vitro rates of formation of the three main oxidative metabolites of antipyrine in man. Br J Clin Pharmacol. 1981 Dec;12(6):771–777. doi: 10.1111/j.1365-2125.1981.tb01305.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Breimer D. D., Honhoff C., Zilly W., Richter E., van Rossum J. M. Pharmocokinetics of hexobarbital in man after intravenous infusion. J Pharmacokinet Biopharm. 1975 Feb;3(1):1–11. doi: 10.1007/BF01066591. [DOI] [PubMed] [Google Scholar]
  4. Breimer D. D. Interindividual variations in drug disposition. Clinical implications and methods of investigation. Clin Pharmacokinet. 1983 Sep-Oct;8(5):371–377. doi: 10.2165/00003088-198308050-00001. [DOI] [PubMed] [Google Scholar]
  5. Buijs W., van Meeteren-Wälchli B., Breimer D. D., van der Gen A. An improved synthesis of 3-hydroxymethylantipyrine using antipyrine as starting material. Arzneimittelforschung. 1986 Mar;36(3):419–421. [PubMed] [Google Scholar]
  6. Dahlqvist R., Bertilsson L., Birkett D. J., Eichelbaum M., Säwe J., Sjöqvist F. Theophylline metabolism in relation to antipyrine, debrisoquine, and sparteine metabolism. Clin Pharmacol Ther. 1984 Jun;35(6):815–821. doi: 10.1038/clpt.1984.118. [DOI] [PubMed] [Google Scholar]
  7. Danhof M., Groot-van der Vis E., Breiner D. D. Assay of antipyrine and its primary metabolites in plasma, saliva and urine by high-performance liquid chromatography and some preliminary results in man. Pharmacology. 1979;18(4):210–223. doi: 10.1159/000137254. [DOI] [PubMed] [Google Scholar]
  8. Danhof M., Krom D. P., Breimer D. D. Studies on the different metabolic pathways of antipyrine in rats: influence of phenobarbital and 3-methylcholanthrene treatment. Xenobiotica. 1979 Nov;9(11):695–702. doi: 10.3109/00498257909042337. [DOI] [PubMed] [Google Scholar]
  9. Godfrey K. Simple linear regression in medical research. N Engl J Med. 1985 Dec 26;313(26):1629–1636. doi: 10.1056/NEJM198512263132604. [DOI] [PubMed] [Google Scholar]
  10. Grant D. M., Tang B. K., Kalow W. Variability in caffeine metabolism. Clin Pharmacol Ther. 1983 May;33(5):591–602. doi: 10.1038/clpt.1983.80. [DOI] [PubMed] [Google Scholar]
  11. Greenblatt D. J., Divoll M., Abernethy D. R., Harmatz J. S., Shader R. I. Antipyrine kinetics in the elderly: prediction of age-related changes in benzodiazepine oxidizing capacity. J Pharmacol Exp Ther. 1982 Jan;220(1):120–126. [PubMed] [Google Scholar]
  12. Grygiel J. J., Birkett D. J. Cigarette smoking and theophylline clearance and metabolism. Clin Pharmacol Ther. 1981 Oct;30(4):491–496. doi: 10.1038/clpt.1981.193. [DOI] [PubMed] [Google Scholar]
  13. Kappas A., Anderson K. E., Conney A. H., Alvares A. P. Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man. Clin Pharmacol Ther. 1976 Dec;20(6):643–653. doi: 10.1002/cpt1976206643. [DOI] [PubMed] [Google Scholar]
  14. Park B. K. Assessment of the drug metabolism capacity of the liver. Br J Clin Pharmacol. 1982 Nov;14(5):631–651. doi: 10.1111/j.1365-2125.1982.tb04950.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Riggs D. S., Guarnieri J. A., Addelman S. Fitting straight lines when both variables are subject to error. Life Sci. 1978 Apr 3;22(13-15):1305–1360. doi: 10.1016/0024-3205(78)90098-x. [DOI] [PubMed] [Google Scholar]
  16. Robson R. A., Miners J. O., Wing L. M., Birkett D. J. Theophylline-rifampicin interaction: non-selective induction of theophylline metabolic pathways. Br J Clin Pharmacol. 1984 Sep;18(3):445–448. doi: 10.1111/j.1365-2125.1984.tb02487.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Teunissen M. W., Bakker W., Meerburg-Van der Torren J. E., Breimer D. D. Influence of rifampicin treatment on antipyrine clearance and metabolite formation in patients with tuberculosis. Br J Clin Pharmacol. 1984 Nov;18(5):701–706. doi: 10.1111/j.1365-2125.1984.tb02532.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Teunissen M. W., De Leede L. G., Boeijinga J. K., Breimer D. D. Correlation between antipyrine metabolite formation and theophylline metabolism in humans after simultaneous single-dose administration and at steady state. J Pharmacol Exp Ther. 1985 Jun;233(3):770–775. [PubMed] [Google Scholar]
  19. Teunissen M. W., Meerburg-van der Torren J. E., Vermeulen N. P., Breimer D. D. Automated high-performance liquid chromatographic determination of antipyrine and its main metabolites in plasma, saliva and urine, including 4,4'-dihydroxyantipyrine. J Chromatogr. 1983 Dec 9;278(2):367–378. [PubMed] [Google Scholar]
  20. Teunissen M. W., Srivastava A. K., Breimer D. D. Influence of sex and oral contraceptive steroids on antipyrine metabolite formation. Clin Pharmacol Ther. 1982 Aug;32(2):240–246. doi: 10.1038/clpt.1982.154. [DOI] [PubMed] [Google Scholar]
  21. Toverud E. L., Boobis A. R., Brodie M. J., Murray S., Bennett P. N., Whitmarsh V., Davies D. S. Differential induction of antipyrine metabolism by rifampicin. Eur J Clin Pharmacol. 1981;21(2):155–160. doi: 10.1007/BF00637517. [DOI] [PubMed] [Google Scholar]
  22. Vesell E. S. New directions in pharmacogenetics: Introduction. Fed Proc. 1984 May 15;43(8):2319–2325. [PubMed] [Google Scholar]
  23. Vesell E. S. The antipyrine test in clinical pharmacology: conceptions and misconceptions. Clin Pharmacol Ther. 1979 Sep;26(3):275–286. doi: 10.1002/cpt1979263275. [DOI] [PubMed] [Google Scholar]
  24. van der Graaff M., Vermeulen N. P., Hofman P. H., Breimer D. D. Correlation of apparent intrinsic clearances of simultaneously administered S (+) and d3R (-) hexobarbital in the rat. Biochem Pharmacol. 1987 Apr 15;36(8):1321–1323. doi: 10.1016/0006-2952(87)90088-8. [DOI] [PubMed] [Google Scholar]
  25. van der Graaff M., Vermeulen N. P., Joeres R. P., Vlietstra T., Breimer D. D. Correlation between the in vivo metabolism of hexobarbital and antipyrine in rats. J Pharmacol Exp Ther. 1983 Nov;227(2):459–465. [PubMed] [Google Scholar]
  26. van der Graaff M., Vermeulen N. P., Langendijk P. N., Breimer D. D. Pharmacokinetics of simultaneously administered hexobarbital and heptabarbital in rats: an alternative approach to metabolic correlation studies. J Pharmacol Exp Ther. 1983 Jun;225(3):747–751. [PubMed] [Google Scholar]

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