Summary
The aim of this work was to study the influence of labelling on caffeine metabolism according to the incubation mode. It has been observed that labelling induces an isotopic effect on metabolisation speed: apparent half-lives are systematically increased. Moreover, isotopic effects are in agreement with those previously observed for retention times. Qualitatively, caffeine labelling systematically induces metabolic variations to the detriment of the metabolic pathway that induces the loss of the trideuteromethyl group. Caffeine accumulation and the release of the main metabolites have been studied with respect to isotopic effects on crossing the cell membrane. It has been demonstrated that, in most of the cases, accumulation decreased and that either metabolite release was increased or no isotopic effect was observed.
Similar content being viewed by others
References
Wiberg K.B. (1955): The deuterium isotope effect. Chem. Rev., 55, 713–743.
Blake M.I., Crespy H.L., Katz J.J. (1975): Studies with deuterated drugs. J. Pharm. Sci., 64, 367–391.
El Tayar N., Van der Waterbeemd H., Gryllaki M., Testa B., Trager W.F. (1984): The lipophilicity of deuterium atoms. A comparison of shake flask and HPLC methods. Intern. J. Pharm., 19, 271–281.
Foster A.B. (1985): Deuterium isotope effects in the metabolism of drugs and xenobiotics: implication for drug design. Adv. Drug Res., 14, 1–36.
Bechalany A., El Tayar N., Carrupt P.A. et al. (1989): Isotope effects on the lipophilicity of deuterated caffeine. Helv. Chim. Acta, 72, 472–476.
Cherrah Y., Zini R., Falconnet J.B., Désage M., Tillement J.P., Brazier J.L. (1988): Study of deuteroisotopomers induced inhibition of caffeine and phenobarbitone binding to human serum albumin. Biochem. Pharmacol., 37, 1311–1315.
Horning M.G., Haegele K.D., Sommer K.R., Nowlin J., Stafford M., Thenot J.P. (1976): Metabolic switching of drug pathways as a consequence of drug substitution. In: Klein E.R., Kelin P.D. (Eds) Proceedings of the 2nd International Conference on Stable Isotopes. New York: Academic Press, 41–54.
Horning M.G., Lertratanangkoon K., Haegele K.D., Brendel K. (1978): Isotope effects on pathways of metabolism. In: Baillie T.A. (Ed) Stable Isotopes — Applications in Pharmacology, Toxicology and Clinical Research, London: McMillan, 55–64.
Tanabe M., Yasuda D., Levalley S., Mitoma C. (1969): The pharmacologic effect of deuterium substitution on 5-n-butyl-5-ethylbarbituric acid. Life Sci., 8, 1123–1128.
Hawkins D.R. (1977): The role of stable isotopes in drug metabolism. In: Bridges J.W., Chasseaud L.F. (Eds) Progress in Drug Metabolism. New York: Wiley, 163–218.
Northrop D.B. (1981): The expression of isotope effects on enzyme-catalyzed reactions. Annu. Rev. Biochem., 50, 103–110.
Korzekwa K.R., Trager W.F., Gilette R. (1989): Theory for the observed isotope effects from enzymic systems that form multiple products via branched reaction pathways: cytochrome P-450. Biochem. J., 28, 9012–9018.
Korzekwa K.R., Gilette R., Trager W.F. (1995): Isotope effects studies on the cytochrome P450 enzymes. Drug Metab. Rev., 24, 45–59.
Cherrah Y., Falconnet J.B., Désage M., Brazier J.L., Zini R., Tillement J.P. (1987): Study of deuterium isotope effects on protein binding by gas chromatography/mass spectrometry. Caffeine and deuterated isotopomers. Biomed. Environ. Mass Spectrom., 14, 653–657.
Falconnet J.B., Désage M., Brazier J.L. (1986): Synthesis of seven deuteromethyl caffeine analogues; observation of deuterium isotope effects on CMR analysis. J. Labelled Compd Rad., 23, 267–276.
Ribon B., Benchekroun Y., Désage M., Riou J.P., Brazier J.L. (1988): Metabolism of caffeine and three of its tri-deuteromethyl isotopomers. Liver Cells Drugs, 64, 269–274.
Benchekroun Y., Désage M., Ribon B., Brazier J.L. (1990): Gas chromatography mass spectrometric quantitation of di, tri and monomethyl xanthines and uric acids from hepatocytes’ incubation media. J. Chromatogr., 532, 264–275.
Heys J.R. (1987): High performance liquid chromatographic studies of pH dependence in the isotopic fractionation of deuterated benzazepines. J. Chromatogr., 407, 37–47.
Scher C., David B., Halevi E.A. (1982): Deuterium isotope effects on the dipole moment and polarizability of hydrogen chloride and ammonia. J. Phys. Chem., 86, 654–658.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Benchekroun, Y., Dautraix, S., Desage, M. et al. Deuterium isotope effects on caffeine metabolism. European Journal of Drug Metabolism and Pharmacokinetics 22, 127–133 (1997). https://doi.org/10.1007/BF03189795
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF03189795