Stereospecificity of Esterases Hydrolyzing Oxazepam Acetate

Maksay, Gábor; Tegyey, Zsuzsanna; Ötvös, László

doi:10.1002/jps.2600670905

Cited by 29 publications

(11 citation statements)

References 16 publications

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“…For example, incubation of DL-threo-methylphenidate in human plasma and red blood cells preparations showed opposite stereoselectivity in the hydrolysis of the two enantiomers (RR/SS ratio approximately 0.31 in plasma, but 1.16 in red blood cells; Srinivas et al, 1991). Other examples of ester-containing chiral drugs showing stereoselective in vitro hydrolysis include esmolol (Quon et al, 1988) and oxazepam (Salmona et al, 1974;Maksey et al, 1978). Therefore, improper sample storage and/or handling of such esterase labile chiral drugs may produce an artefactual discrepancy in the ratios of the enantiomers.…”

Section: Reviewmentioning

confidence: 99%

Clinical pharmacokinetic data of racemic drugs obtained by the indirect method following precolumn diastereomer formation: is the influence of racemization during chiral derivatization significant?

Srinivas¹

2004

Biomedical Chromatography

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This report reviews the stereoselective data of a number of racemic drugs (n = 17) obtained from indirect chiral method (via diastereomer formation) in comparison to similar data generated by the application of a direct chiral method. While it was noted that the indirect method still continued to be used to characterize the stereoselective disposition of racemic drugs, the present review critically evaluates the issue of racemization that has the potential to skew the stereoselective data obtained from the indirect method. The review describes various remedies to counter and/or minimize the impact of racemization on the final outcome of the stereoselective analysis by the indirect method. On the basis of this review it could be concluded that the indirect method is a viable and important tool for gathering stereoselective data of racemic drugs used in medical practice as well for those racemic drugs still in discovery and developmental stages.

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Section: Reviewmentioning

confidence: 99%

Clinical pharmacokinetic data of racemic drugs obtained by the indirect method following precolumn diastereomer formation: is the influence of racemization during chiral derivatization significant?

Srinivas¹

2004

Biomedical Chromatography

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“…Stereoselective hydrolysis of ester prodrugs including PL prodrugs is largely dependent on the type of species and the tissue of origin. [20][21][22][23][24][25] Variability in the esterase content may have a significant effect on the rate of regeneration, tissue uptake, and disposition of the prodrug. Thus, consideration of stereoselectivity during prodrug design is very important.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, stereoselective enzymatic hydrolysis, and skin permeation of diastereomeric propranolol ester prodrugs

Udata¹,

Tirucherai²,

Mitra³

1999

Journal of Pharmaceutical Sciences

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Four diastereomeric propranolol ester prodrugs (1S2S, 1S2R, 1R2S, 1R2R) were synthesized by treating pure R- and S-propranolol hydrochloride with pure enantiomers R- and S-phenylbutyryl chloride. A HPLC technique using alpha-1 acid glycoprotein (chiral AGP) column was developed to study the racemization of propranolol enantiomers during synthesis and hydrolysis studies. A reversed phase HPLC method was also developed to simultaneously analyze propranolol and the ester prodrug. Hydrolysis of these esters was studied in different rat tissue homogenates, i.e., liver, intestine, plasma, skin, brain, and pure plasma cholinesterases, i.e., butyryl cholinesterase (EC 3.1.1.8) and acetyl cholinesterase (EC 3.1.1.7). In vitro percutaneous permeation studies across full thickness shaved rat skin were performed using standard side-by-side diffusion cells at 37 degrees C. The disappearance of the diastereomeric ester prodrugs in rat tissue homogenates followed apparent first-order kinetics and was stereoselective. The ratio of brain to plasma hydrolytic rate constants are 27.8, 5.58, 6.07, and 2.97 for 1S2S, 1R2R, 1R2S, and 1S2R esters, respectively. Hydrolysis of all four diastereomeric ester prodrugs was faster by acetyl cholinesterase than butyryl cholinesterase and is stereoselective. The permeability coefficients [Kp x 10(3) (cm h-1)] are 1.40 +/- 0.30, 1.41 +/- 0.27, 42.20 +/- 1.24, 29.26 +/- 3.41, 16.27 +/- 3.12, 12.99 +/- 2.84 for (R)-propranolol, (S)-propranolol, 1S2S, 1R2S, 1S2R, and 1R2R ester prodrugs, respectively. The results indicate that the 1R2S diastereomeric ester prodrug of propranolol shows greatest stability in liver and intestinal tissues while it exhibits fairly rapid conversion in plasma. The results also suggest the configuration on the second chiral carbon atom to be the determinant in the rate of hydrolysis of all the diastereomeric prodrugs in all biological media examined. The Kp of all four prodrugs markedly increased compared to that of the parent drug, with 1S2S showing a 30-fold increase in skin permeability, the highest among all four prodrugs.

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“…E.g. the acetic and hemisuccinic esters of oxazepam are effective prodrug derivatives (2,3). As the metabolism of the esters proceeds by their hydrolysis and the consecutive conjugation tõ -glucuronides (3)(4)(5), a comparison of the hydrolysis rates of 3-acyloxy-benzodiazepines provides information on the rates of bioactivation.…”

Section: Introductionmentioning

confidence: 99%

“…Hungary. esterase activity of the tissue fractions (3). Further it was shown that the brain penetration of liberated oxazepam correlates with the microsomal hydrolysis rates of its esters (6).…”

Section: Introductionmentioning

confidence: 99%

Structural parameters in the microsomal hydrolysis of 3-acyloxy-l, 4-benzodiazepines and the multiplicity of the esterases involved

Maksay

Tegyey

Simon‐Trompler

et al. 1980

European Journal of Drug Metabolism and Pharmacokinetics

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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 sigma* and hydrophobic deltaRM terms of the acyl moiety. The role of the polar term shows that a nucleophilic attack of the acyl moiety determines the hydrolysis. The role of hydrophobicity can be attributed to its interrelation with the steric parameter. The common equations for the aliphatic sters of oxazepam and larazepam suggest the similar nature of the esterases in question and the same catalytic mechanism. Different 3-acetoxy-1, 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.

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Stereospecificity of Esterases Hydrolyzing Oxazepam Acetate

Cited by 29 publications

References 16 publications

Clinical pharmacokinetic data of racemic drugs obtained by the indirect method following precolumn diastereomer formation: is the influence of racemization during chiral derivatization significant?

Clinical pharmacokinetic data of racemic drugs obtained by the indirect method following precolumn diastereomer formation: is the influence of racemization during chiral derivatization significant?

Synthesis, stereoselective enzymatic hydrolysis, and skin permeation of diastereomeric propranolol ester prodrugs

Structural parameters in the microsomal hydrolysis of 3-acyloxy-l, 4-benzodiazepines and the multiplicity of the esterases involved

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