Enantioselectivity, drug metabolism

Chiral CE with CyDs as chiral selectors can be used to evaluate the enantiomeric purity of chiral chemicals, agrochemicals, food additives, pharmaceuticals, and drug formulations as well as for investigations of endogenous compounds and enantioselective drug metabolism and pharmacokinetics [51, 52]. A few selected examples of applications of chiral CE with CyDs as chiral selectors as well as of mechanistic studies on CyD-analyte interactions are mentioned below. 

Lin JH, DeLuna FA, Ulm EH, Tocco DJ (1990) Species-dependent enantioselective plasma protein binding of MK-571, a potent leukotriene D4 antagonist. Drug Metabolism Disposition 18 484... 

Enantioselectivity in Drug Metabolism Lawrence K. Low, Neal Castagnoli, Jr. 13, 304... 

Enantioselectivity in Drug Action and Drug Metabolism The Beginnings... 

Kroemer, H. K., Gross, A. S., Eichelbaum, M. Enantioselectivity in drug action and drug metabolism influence on dynamics. In Pharmacodynamics and Drug Development (Cutler, N. R., Sramek, J. J., Narang, P. K., Eds). John Wiley Sons Chichester, 1994, pp. 103-114. 

In drug metabolism, stereodifferentiation is the rule rather than the exception, and stereoselectivity in metabolism is probably responsible for the majority of the differences observed in enantioselective drug disposition. Stereoselectivity in metabolism may arise from differences in the binding of enantiomeric substrates to the enzyme active site and/or be associated with catalysis owing to differential reactivity and orientation of the target groups to the catalytic site [106]. As a result, a pair of enantiomers are frequently metabolized at different rates and/or via different routes to yield alternative products. 

Kim, M. Shen, D.D. Eddy, A.C. Nelson, W.L. Roskos, L.K. Inhibition of the enantioselective oxidative metabolism of metoprolol by verapamil in human liver microsomes. Drug Metab. Dispos. 1993, 21, 309-317. 

The latter approach is used in the enantioselective determination of a Phase I metabolite of the antihistaminic drug, terfenadine. Terfenadine is metabolized to several Phase I compounds (Fig. 7-13), among which the carboxylic acid MDL 16.455 is an active metabolite for which plasma concentrations must often be determined. Although terfenadine can be separated directly on Chiralpak AD - an amy-lose-based CSP - the adsorption of the metabolite MDL 16.455 is too high to permit adequate resolution. By derivatizing the plasma sample with diazomethane, the carboxylic acid is converted selectively to the methyl ester, which can be separated in the presence of all other plasma compounds on the above-mentioned CSP Chiralpak AD [24] (Fig. 7-14). Recently, MDL 16.455 has been introduced as a new antihistaminic drug, fexofenadine. 

Carboxylesterases and amidases catalyze hydrolysis of carboxy esters and carboxy amides to the corresponding carboxylic acids and alcohols or amines. In general those enzymes capable of catalyzing hydrolysis of carboxy esters are also amidases, and vice versa (110). The role of these enzymes in metabolsim of drugs and insecticides has been reviewed (111, 112). In addition to the interest in mammalian metabolism of drugs and environmental chemicals, microbial esterases have been used for enantioselective hydrolyses (113, 114). 

Racemic warfarin (65), a vitamin K antagonist, has been used for decades both as an oral anticoagulant in man and as a rodenticide. The metabolism of this drug has been found to be substrate-enantioselective 9S-warfarin is considered as more active than the 9R-antipode. In mammalian systems, warfarin undergoes a stereoselective reduction of the ketonic side chain [176,177], affording mainly the 9R,llS-alcohol (71), but the major biotransformation route involves substrate-enantioselective aromatic hydroxylations at 4 -, 6-, 7- or 8-positions... 

Plasma is the most frequently analyzed matrix, and enantioselective determination of a parent drug for pharmacokinetic and therapeutic monitoring the most frequent goal of the developed methods but assays with simultaneous determination of metabolism are also common (Table 17.5). The majority of the methods are based on MS detection, and ESI is the predominant ionization... 

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. 

Enantiomeric Pairs. Enantioselective differences in absorption, metabolism, clearance, drug-macromolccule binding affinity, and other factors, which culminate in the obscivcd enantioselective efficacy chiral drugs, are considered. 

Ketamine, a dissociative anaesthetic, is administered as a racemic mixture (present in the parenteral preparation) and is initially metabolized by the liver to AT-desmethylketamine (metabolite I), which in part is converted by oxidation to the cyclohexene (metabolite II) (Fig. 1.5). The major metabolites found in urine are glucuronide conjugates that are formed subsequent to hydroxylation of the cyclohexanone ring. As the enantiomers differ in anaesthetic potency and the enantioselectively formed (metabolite I has approximately 10% activity of the parent drug) interpretation of the relationship between the anaesthetic effect and disposition of ketamine is complicated. On a pharmacodynamic basis, the S(+) enantiomer is three times as potent as the R(-) enantiomer (Marietta et al., 1977 Deleforge et al., 1991), while the enantiomer that undergoes N-demethylation (hepatic microsomal reaction) differs between species (Delatour et al, 1991). Based on the observed minimum anaesthetic... 

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