Enantioselective metabolism

Simoni S, S Klinke, C Zipper, W Angst, H-P E Kohler (1996) Enantioselective metabolism of chiral 3-phenyl-butyric acid, an intermediate of linear alkylbenzene degradation, by Rhodococcus rhodochrous. Appl... 

Enantioselective metabolism oxidative deamination and reduction to 2-ol (R) benzylic 2 -methyl hydroxylation C-3 or 4 aromatic hydroxylations (S)... 

Racemic methadone (MET) is administered to heroin addicts as a substitution therapy. However, methadone enantiomers possess different pharmacological effects, and the drug has been demonstrated to be enantioselectively metabolized to its two major metabolites, 2-ethylidene-l,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl-l-pyrroline (EMDP). Stereoselective separation of MET, EDDP, and EMDP using an alpha-glycoprotein stationary phase and MS-MS detection was proposed by Kelly et al. [34]. Optimal separation conditions were 20 mM acetic acid isopropanol (93 7, pH 7.4), with a flow rate of 0.9mL/min. 

The enantioselective metabolism of optically active thalidomide (1) has recently been intensively investigated (Scheme 16) [80]. While the (S)-isomer is found to be metabolized preferentially by hydroxylation of the phthaloyl ring, the (A)-isomer undergoes metabolic hydroxylation in the dioxopiperidine ring. Although it is impossible to find the relationship between the teratogenicity and enantioselective metabolism of thalidomide (1), the application of racemic thalidomide (1) in therapy is clearly controversial [81-84]. 

Scheme 16 The enantioselective metabolism of optically active thalidomide (1) [80]...

Ellis SW, Rowland K, Harlow JR, et al. Regioselective and enantioselective metabolism of metoprolol by 2 human cDNA-derived Cyp2d6 proteins. Br J Pharmacol 1994 112 U124-U124. 

Capillary gas chromatographic determination of optical purities, investigation of the conversion of potential precursors, and characterization of enzymes catalyzing these reactions were applied to study the biogenesis of chiral volatiles in plants and microorganisms. Major pineapple constituents are present as mixtures of enantiomers. Reductions, chain elongation, and hydration were shown to be involved in the biosynthesis of hydroxy acid esters and lactones. Reduction of methyl ketones and subsequent enantioselective metabolization by Penicillium citrinum were studied as model reactions to rationalize ratios of enantiomers of secondary alcohols in natural systems. The formation of optically pure enantiomers of aliphatic secondary alcohols and hydroxy acid esters using oxidoreductases from baker s yeast was demonstrated. 

Regiospecific and enantioselective metabolism of 8,9-epoxyeicosatrienoic acids by cyclooxygenase. Biochem. Biophys. Res. Commun. 183, 138-143. 

Takahashi, H. Sato, T. Shimoyama, Y. Shioda, N. Shimizu, T. Kubo, S. Tamura, N. Tainaka, H. Yasumori, T. Echizen, H. Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the uricosuric agent benzbromarone. Clin. Pharmacol. Ther. 1999, 66, 569-581. 

Xiaotao, Q. Hall, S.D. Modulation of enantioselective metabolism and inversion of ibuprofen by xenobiotics in isolated rat hepatocytes. J. Pharmacol. Exp. Ther. 1993, 266, 845-851. 

A classic method of demonstrating enantioselective first-pass metabolism is to administer the racemic drug orally and i.v. in a crossover study and then evaluate the PK of each enantiomer using a stereospecific assay. Stereoselective first-pass metabolism is indicated by significantly different absolute bioavailabilities of the enantiomers. This approach was used to establish low enantioselective first-pass metabolism of ketoprofen [56] and high enantioselectivity of propranolol [38,42] and verapamil [44,45,53]. Enantioselective metabolism of propranolol and verapamil has been studied extensively and found to be influenced by age and gender [40,50]. With verapamil, changes in plasma enantiomeric ratios after administration... 

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