Summary
The enzymatic splitting and metabolic elimination of anti-viral agent 5-(2-chloroethyl)-2′-deoxyuridine [CEDU] have been studied. For elucidation of structures of metabolites, several different kinds of extraction, purification and spectroscopic methods were used (Extrelut LC, TLC, HPLC, MS, NMR, IR, UV and CD). For mass spectral analysis, various ionization techniques (EI, CI and FAB-MS) were performed as complementary methods. After oral administration of [1 4C]-CEDU to mice and rats, the parent compound, 5-(2chloroethyl) uracil [CEU] and hydroxylated CELT metabolites were isolated and identified from urine and faeces by the above mentioned methods.
The CEDU showed rapid phosphorolysis in vitro with thymidine Phosphorylase Km 10.0 ± 5.0; and uridine Phosphorylase Km 10.0 ± 1.5. The cleavage of the N-glycosidic bond of the nucleoside analogue and a new metabolic pathway of CEDU [stereoselective oxidation of 5-(2-chloroethyl) uracil] was observed in both species.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
De Clercq E. (1984): Pyrimidine nucleoside analogues as antiviral agent In: De Clercq E., Walker R.T. Eds. New York, Plenum, pp. 203–230.
Desgranges C., De Clercq E., Razaka G., Drouillet F., Belloc I., Bricaud H. (1986): Deoxyribosyl exchange reactions leading to the in vivo generation and regeneration of the antiviral agents (E)-S-(2-bromovinyl)-2′-deoxyuridine, S-ethyl-2′-deoxyuridine and 5-(2-chloroethyl)-2′-deoxyuridine. Biochem. Pharmacol, 35, 1647–1653.
Veres Zs., Szinai I., Szabolcs A., Ujszaszy K., Denes G., (1987): Biological activity of the potent uridine Phosphorylase inhibitor 5-ethyl-2,2′-anhydrouridine. Drugs Exp. Clin. Res., XIII, 7068–7074.
Desgranges C., Razaka G., Drouvillet F., Bricaud H., Herdewijn P., De Clercq E. (1984): Regeneration of the antiviral drug (E)-5-(2-bromoviny)-2′-deoxyuridine in vivo. Nucl. Acids Res., 12, 2081–2090.
Veres Zs., Szabolcs A., Szinai I., Denes G., Jeney A. (1986): Enzymatic cleavage of 5-substituted-2′-deoxyuridines by pyrimidine nucleoside phosphorylases. Biochem. Pharmacol., 35, 1057–1059.
Griengl H., Bodenteich M., Hayden W., et al. (1985): 5-(haloalkyl)-2’-deoxyuridines. A novel type of potent antiviral nucleoside analogue. J. Med. Chem., 28, 1679–1684.
De Clercq E., Rosenwirth B. (1985): Selective in vitro in vivo activities of 5-(2-haloalkyl)pyrimidine nucleoside particularly 5-(2-chloroethyl)-2′-deoxyuridine, against herpes simplex virus. Antimicrob. Agents Chemother., 28, 246–251.
Rosenwirth B., Griengl H., Wanek E., De Clercq E. (1985): 5-(2-chloroethyl)-2′-deoxyuridine, a potent and selective inhibitor of herpes viruses in vitro and in vivo. Antiviral Res. Suppl., 1, 21–28.
Maudgal P.C., De Clercq E., Bemaerts R., Dieltiens M., Breemersch M., van Eeckhoutte L. (1986): Ocular penetration and efficacy of chloroethyl deoxyuridine against herpes keratouveitis. Invest. Ophthalmol. Vis. Sci., 27, 1453–1458.
Griengl H., Schwarz W., Schatz F., Skrobal M., Werner G., Rosenwirth B. (1986): Synthesis and antiviral activity of S′-O and 3-N substituted derivatives of 5-(2-chloroethyl)-2′-deoxyuridine. Chemica Scripta, 26, 67–71.
Gacs I., Vargay Z., Dobis E., Dombi S., Payer K., Otvos L. (1982): A new automatic combustion method for the liquid scintillation assay of tritium and carbon-14 in singly or doubly labelled organic materials. I. Radioanal. Chem., 68, 93–98.
Ganzler K., Salgo A., Valko K. (1986): Microwave extraction: a novel sample preparation method for chromatography. J. Chromatogr., 371, 299–306.
Desgranges C., Razaka G., Raboud M., Bricaud H., Balzarini J., De Clercq E. (1983): Phosphorolysis of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) and other 5 substituted 2′-deoxyuridines by purified human thymidine phosphorylase and intact blood platelets. Biochem. Pharmacol., 32, 3583–3590.
Jenner P., Testa B. (1973): Influence of stereochemical factors on drug disposition. Drug Metab. Rev., 2, 117–184.
Testa B. (1984): Chiral aspects of drug metabolism. TIPS Rev, 60–64.
Szinai I., Bihari M., Ujszaszy K., et al. (1984): Biotransformation of 5-ethyl and 5-isopropyl-2′-deoxyuridines in mice and rats. In. Bioorganic Heterocycles Synthetic Physical Organic and Pharmacological Aspects, Van der Pias H.C., Otvos L. Simonyi M. Eds. Amsterdam, Elsevier, pp. 335–337.
Szinai I., Bihari M., Ujszaszy K., Veres Zs., Szabolcs A., Otvos L. (1984): Biotransformation of 5-ethyl-2′-deoxyuridine and 5-ethyluracil in mice and rats. FEBS. XTV. Meeting Moscow, XXH-146 464.
Von Kaul R., Hempel B. (1985): Isolation and identification of the metabolites of 5-ethyl-2′-deoxyuridine from rat urine. Airaeimittelforsch., 35, 1055–1057.
Szinai I., De Clercq E. (1989): Biotransformation of 5-(2-chloroethyl)-2′-deoxyuridine in male NMRI mice. Drug Metab. Dipos., 17, 683–689.
Marquard H., Wertendorff J., Schaefer A., Boldt J., De Clercq E. Marguadt H. (1988): Mutagenic and antimutagenic effects of 5-substituted-2′-deoxyuridines depending on the nature of 5-substituent. Arzneimittelforsch., 38, 1820–1824.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Szlnai, I., Veres, Z., Ganzler, K. et al. Metabolism of anti-herpes agent 5-(2-chloroethyl)-2′-deoxyuridine in mice and rats. European Journal of Drug Metabolism and Pharmacokinetics 16, 129–136 (1991). https://doi.org/10.1007/BF03189949
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF03189949