Summary
The biotransformation of several prodrug-type esters of centrally acting 1, 4-benzodiazepines was studied. Their rates of hydrolysis catalyzed by the hepatic microsomal fraction of mice were measured by pH-stat. The heterogeneity of the microsomal esterases was investigated with induction by phenobarbital and with inhibition by DFP. The resulting changes in esterase activity indicated that the phenyl-substituted esters separate from the homogenous sets of oxazepam and lorazepam esters. Regression analysis of the relative hydrolysis rates of the homogenous ester sets revealed a similar dependence on the steric ES′ the polar σ* and hydrophobic ΔR M terms of the acyl moiety. The role of the polar term shows that a nucleophilic attack of the acyl moiety determines the hydrolysis rate. The role of hydrophobicity can be attributed to its interrelation with the steric parameter. The common equations for the aliphatic esters of oxazepam and larazepam suggest the similar nature of the esterases in question and the same catalytic mechanism. Different 3-acetoxy-l, 4-benzodiazepines were also synthetised and their maximal hydrolysis rates were quite different. This excludes the possibility that the deacylation step of the enzymes is rate-determining. Instead, our data suggest that acylation of the microsomal esterases is rate-limiting for the hydrolysis of the aliphatic esters of 3-OH-benzodiazepines.
Similar content being viewed by others
References
Marcucci, F., Mussini, E., Airoldi, L., Guaitani, A. and Garattini, S. (1972): Brain concentrations of lorazepam and oxazepam at equal degree of anticonvulsant activity. J. Pharm. Pharmac.24. 63–64.
Lescovelli, M., Castellani, A. and Pertellini, D. (1976): A double-blind cross-over evaluation of the activity of D-oxazepam hemisuccinate sodium salt compared to its racemic form. Arzneim. -Forsch.26, 1623–1626.
Maksay, G., Tegyey, Z. and Ötvös, L. (1978): Stereospecificity of esterases hydrolyzing oxazepam acetate. J. Pharm. Sei.,67, 1208–1210.
Walkenstein, S.S., Wiser, R., Gudmundsen, C.H., Kimmel, H.B. and Corradino, R.A. (1964): Absorption, metabolism and excretion of oxazepam and its succinate half-ester. J. Pharm. Sei.,53, 1181–1186.
Sanchez, M.C., Colomé, J. and Gelpi, E. (1976): Electron capture and multiple ion detection of benzodiazepine esters in pharmacokinetic studies.
Maksay, G., Tegyey, Z., Kemény, V., Lukovits, I. and Ötvös, L. (1979): Oxazepam esters. I. Correlation between hydrolysis rates and brain appearance of oxazepam. J. Med. Chem.,22, 1436–1443.
Maksay, G., Tegyey, Z. and Ötvös, L. (1978): Kinetic investigations of liver microsomal esterases with oxazepam esters. Hoppe Seyler’s Z. Physiol. Chem.359, 879–886.
Bell, S.C. and Childress, S.J. (1962): A rearrangement of 5-aryl-l, 3-dihydro-2H-l, 4-benzodiazepine-2-one 4-oxides. J. Org. Chem.27, 1691–1695.
Ditterbrandt, M. (1948): Application of the weichelbaum biuret reagent to the determination of spinal-fluid protein. Am. J. Clin. Pathol.18, 439–441.
Maksay, G., Tegyey, Z. and Ötvös, L. (1979): Structure-RM investigation of 3-acyloxi-1,4-benzodiazepines. J. Chromatogr.174, 447–450.
Hansch, C., Muir, R.M. Fujita, T., Maloney, P.P., Geiger, F. and Streich, M. (1963): The correlation of biological activity of plant growth regulators and Chloromycetin derivatives with Hammet constants and partition coefficients. J. Amer. Chem. Soc.85, 2817- 2824.
Hansch, C., Lien, E.J. and Helmer, F. (1968): Structure-activity correlation in the metabolism of drugs. Arch. Biochem. Biophys.128, 319–330.
Taft, R.W. (1956): Separation of polar, steric and resonance effects. In: Steric Effects in Organic Chemistry, ed. M.S. Newman, John Wiley and Sons, Inc., New York, pp. 556–675.
Charton, M. (1977): The prediction of chemical lability trough substituent effects. In: Des. Biopharm. Prop. Prodrugs Analogs (Symp.), ed. E.B. Roche, Am. Pharm. Assoc., Washington, D.C., pp. 228–280.
Mendoza, C.E. and Hatina, G.V. (1971): Comparative starch -gel electrophoresis of liver esterases from seven species. Comp. Biochem. Physiol.39 B, 483–488.
Carruthers, C., Heins, E., Baumler, A. (1965): Fractionation of mouse liver microsomal esterases. Can. J. Biochem.43, 97–104.
Lu, A.Y.H., Levin, W., West, S.B., Jacobson, M., Ryan, D., Kuntzman, R. and Conney, A.H. (1973): Reconstituted liver microsomal enzyme system that hydroxylates drugs, other foreign compounds and endogenous substrates. VI. Different substrate specificities of the cytochrome P-450 fractions from control and phenobarbital-treated rats.
Fasco, M.J., Piper, L.J. and Kaminsky, L.S. (1979): Cumene hydroperoxide-supported microsomal hydroxilations of warfarin.- A probe of Cytochrom P-450 multiplicity and specificity. Biochem. Pharmacol.28, 97–103.
Raftell, M., Berzins, K. and Blomberg, F. (1977): Immunochemical studies on a phenobarbital-inducible esterase in rat liver microsomes. Arch. Biochem. Biophys.181, 534–541.
Lundkvist, V. and Perlmann, P. (1966): Immunochemical studies of submicrosomal membrames from liver of normal and phenobarbital-treated rats. Science,152, 780–782.
Al-Gailany, K.A.S., Houston, J.B. and Bridges, J.W. (1978): The role of substrate lipophilicity in determining type I microsomal P-450 binding characteristics. Biochem. Pharmacol.27, 783–2788.
Kirsch, J.F. (1972): Linear free energy relationships in enzymology. In: Advances in Linear Free Energy Relationships, ed. N.B. Chapman and J. Shorter, Plenum Press, London, New York, pp. 369–400.
Craig, P.N. (1971): Interdependence between physical parameters and selection of substituent groups for correlation studies. J. Med. Chem.14, 680–684.
Jencks, W.P. (1969): Catalysis in Chemistry and Enzymology, Mc. Graw-Hill, New York, p. 52.
Kristofferson, J., Svensson, L. A. and Tegner, K. (1974): Drug latentiation of terbutaline. In vitro serum esterase catalyzed hydrolysis of a series of acyl-substituted mono and diesters of terbutaline. Acta Pharm. Suecica11, 427–438.
Testa, B. (1978): QSAR in drug metabolism and disposition. An application to the affinity for cytochrome P-450 and hepatic clearance of barbiturates. Pharm. Acta Helv.53, 143–146.
Schwandt, H.J., Sadée, W., Beyer, K.H. and Hildebrant, A.G. (1976): Effects of enzyme induction and inhibition on microsomal oxidation of 1, 4-benzodiazepines. Naunyn Schmiedeberg’s Arch. Pharmacol294 91–97.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Maksay, G., Tegyey, Z., Simon-Trompler, E. et al. Structural parameters in the microsomal hydrolysis of 3-acyloxy-l, 4-benzodiazepines and the multiplicity of the esterases involved. European Journal of Drug Metabolism and Pharmacokinetics 5, 193–200 (1980). https://doi.org/10.1007/BF03189464
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF03189464