Antipodes, metabolism

Biocatalytic access to both antipodal sulfoxides was exploited in total syntheses of bioactive compounds, which is outlined in some representative examples. Biooxidation of functionalized dialkyl sulfides was utilized in the direct synthesis of both enantiomers of sulforaphane and some analogs in low to good yields and stereoselectivities (Scheme 9.27) [206]. This natural product originates from broccoli and represents a potent inducer of detoxification enzymes in mammalian metabolism it might be related to anticarcinogenic properties of plants from the cruciform family. All four possible stereoisomers of methionine (R = Me) and ethionine sulfoxides... 

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... 

It is usual in humans for the S(+)-enantiomer of 2-arylpropionic acids to predominate in plasma and for the S(- -)- to R(-)-enantiomeric ratio of plasma concentrations to increase with time after administration of the racemate, which is often attributed to metabolic inversion of the chiral center of the R( )-enantiomers to their S(- -)-antipodes. ° In humans, the S(- -)-enantiomer is generally eliminated more slowly than is the R( )-enantiomer. The extent of chiral inversion of fenoprofen, which has been attributed to the differential rate of formation of the CoA-thioester by hepatic microsomes, varies widely among species. It has been estimated to be 90% in dogs, 80% in sheep, 73% in rabbits, 60% in humans, 42% in rats,f and 38% in horses. ... 

Keberle, H., Riess, W., Hoffman, K. The stereospecific metabolism of the optical antipodes of (3-phenyl-(3-ethylglutarimide (Doriden). Arch. Int. Pharmacodyn. 1963, 142, 117-124. 

Both enantiomers of the racemic 11,17-diketone (428) were reduced by Rhodotorula ntucilaginosa to 17S-alcohols, but the antipode having 13S-chirality was further reduced to the 11-alcohol Reoxidation then afforded the enantiomeric forms of (428). Similar high stereospecificity was observed in the microbiological reduction of 6,7-dihydro-(428), where reduction of the 11-ketone in the 13S,17S-antipode occurred to give the allylic alcohol Further examples of the differential metabolism of racemic 19-nortestosterone and its 13-ethyl homologue by Curvularia lunata have been described. ... 

The resolution of synthetic presqualene and prephytoene alcohols via their etienic acid derivatives has been reported. This work confirmed that the active (-f-)-enantiomers in both series have the same absolute configuration [(li , 2/ , 3/ )]. It has been established, by use of Hn.m.r., that the proton (deuteron) introduced at C-3 during the cyclization of squalene to tetrahymanol by Tetrahymena pyriformis has the 3/8 configuration. Both antipodes of the trimethyldecalol (13) have been shown to be effective inhibitors of cholesterol biosynthesis in rat liver enzyme preparations and cultured mammalian cells. The accumulation of squalene 2,3-oxide and squalene 2,3 22,23-dioxide in the treated systems indicates that inhibition occurs at the cyclization stage. The inhibitor is metabolized to the diol (14). The results of other sterol inhibition... 

The metabolism of sparteine by humans produces as the chief products 2-and 5-dehydrosparteine as well as 2- and 7-oxo derivatives [124, 125]. Somewhere less than 10% of the Caucasian population have little ability to metabolize it at all [126, 127, 128]. Pachycarpine, the optical antipode of (-)-sparteine is converted in rats to (+)-(4S)-hydroxysparteine as the major product [129]. 

The levo isomers of 3-hydroxy-Af-methyl-morphinan and of methadone are demethylated by rat liver two to three times more rapidly than the corresponding dextro antipodes. The S(-l-)-enantiomer of hexobarbital (Fig. 17.4) is metabolized almost twice as rapidly as the R(— )-enantio-mer by allylic hydroxylation and, in the dog, the dextrorotatory isomer of 5-ethyl-5-phenyl-hydantoin affords ten times more p-hydroxy-metabolite than the levorotatory isomer. Hydroxylation takes place alpha to a carbonyl in the dextrorotary enantiomer of glutathimide, whereas the... 

Stereoselective metabolism is the most important process responsible for the stereoselectivity observed in pharmacokinetics. Verapamil has received considerable attention as an example of substrate stereoselective pharmacokinetics in humans. After oral administration, the drug undergoes an important stereoselective first pass metabolism, so that (— )-verapamil, the active enantiomer, has a two to three times lower bioavailability than its antipode. The (— )/(-f) plasma concentration ratio is therefore higher after intravenous than after oral administration. 

Enantiomers also are referred to as chiral compounds, antipodes, or enantiomorphs. When introduced into an asymmetric, or chiral, environment, such as the human body, enantiomers will display different physicochemical properties, producing significant differences in their pharmacokinetic and pharmacodynamic behavior. Such differences can result in adverse side effects or toxicity, because one or more of the isomers may exhibit significant differences in absorption (especially active transport), serum protein binding, and metabolism. With the latter, one isomer may be converted into a toxic substance or may influence the metabolism of another drug. To discuss further the influence of stereochemistry on drug action, some of the basic concepts of stereochemistry need to be reviewed. 

In humans given racemate or individual enantiomers of thalidomide by the oral route, stereoselective differences were noted in the plasma concentrations of the enantiomers [45]. In cases where the enantiomers were given alone, presence of antipode was detected in each group. After R(+) thalidomide or S(—) thalidomide alone, the R S AUC ratios were 3.0 and 0.74, respectively. After racemate, the R S ratio was 1.6. It was concluded that in addition to the interconversion of enantiomers, which was equal in both directions, the S enantiomer is preferentially metabolized in vivo [45]. 

In general, despite lower free fraetion, S-warfarin is more rapidly eliminated than its antipode in humans, and hepatic metabolism acconnts for almost all of the elimination of the drug [60]. Warfarin is metabolized to 6-hydroxywarfarin, 7-hydroxywarfarin, and two rednced derivatives, the diastereomers of warfarin alcohol [60]. The metabolism of R-warfarin involves oxidation to 6-hydroxywarfarin and subseqnent reduction to (R,S)-warfarin alcohol. In contrast, S-warfarin is oxidized to 7-hydroxywarfarin and reduced to (S,S)-warfarin alcohol. The metabolic profiles of warfarin enantiomers in blood and urine were similar [53,60]. The ring-hydroxylated metabolites are inactive, and the activity of warfarin alcohols are snb-stantially less than the parent molecule [53,60]. S-warfarin may also be metabolized to 6-hydroxywarfarin [60]. 

Zileuton reportedly undergoes stereoselective glucuronidation at a N-hydroxy group. Sweeny et al. [131] showed that the human microsomal glucuronidation rates for the S enantiomer were 3.6 to 4.3 times greater than for antipode. The consequence of stereoselective metabolism is apparent in vivo with 49 to 76% faster clearance of S-zileuton after single oral doses of 200 to 800 mg in normal healthy subjects [130]. Furthermore, it has been demonstrated that each enantiomer of zileuton competitively inhibits the phase II metabolism of respective antipode [131]. 

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