Enantioselective sulfation of ?2-receptor agonists by the human intestine and the recombinant M-form phenolsulfotransferase

Hartman, Andrew P.; Wilson, Anne A.; Wilson, Hugh M.; Åberg, Gunnar; Falany, Charles N.; Walle, Thomas

doi:10.1002/(sici)1520-636x(1998)10:9<800::aid-chir4>3.0.co;2-v

Cited by 21 publications

(8 citation statements)

References 15 publications

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“…Enantioselective phase II metabolism in glucuronidation and sulfation has also been reported in the literature [28][29][30][31][32]. Propranolol, used as a racemic mixture in the treatment of hypertension, is metabolized via glucuronidation and side-chain/ring oxidation [28].…”

Section: Enantioselective Metabolism By Other Enzymesmentioning

confidence: 99%

“…Isoprenaline had a K m value six-times higher for active (R)-isomer than for inactive (S)-enantiomer with V max being comparable between the two enantiomers. However, for albuterol, the stereoselectivity was dramatically reversed with 10-times higher K m for inactive the (S)-enantiomer, but with comparable V max [31,32].…”

Section: Enantioselective Metabolism By Other Enzymesmentioning

confidence: 99%

“…Stereoselectivity in pharmacokinetics is observed for albuterol with a faster disappearance of active (R)-enantiomer from human plasma irrespective of the route of administration [31,32,37]. This is mainly due to the enantioselective metabolism of albuterol in favor of (R)-enantiomer, and this isomer has a 10-fold higher intrinsic clearance value than its antipode [31,37].…”

Section: Enantioselective First-pass Metabolism and Oral Bioavailabilitymentioning

confidence: 99%

“…This is mainly due to the enantioselective metabolism of albuterol in favor of (R)-enantiomer, and this isomer has a 10-fold higher intrinsic clearance value than its antipode [31,37]. Furthermore, the degree of stereoselectivity was highly dependent on the route of administration, with the lowest concentration of (R)-albuterol observed after oral administration.…”

Section: Enantioselective First-pass Metabolism and Oral Bioavailabilitymentioning

confidence: 99%

“…The enantiomeric discrimination in drug disposition depends on the mechanism of the process under consideration. In general, the passive processes in absorption, distribution and [15,16] ± Acenocoumarol 6-Hydroxylation 7-Hydroxylation 8-Hydroxylation CYP2C9 (S >> R); CYP2C19 (R > S) CYP2C9 (S >> R); CYP2C19 (R > S) CYP2C9 (S >> R); CYP2C19 (R > S) [17] ± Ifosfamide 4-Hydroxylation N2-dechloroethylation N 3 -dechloroethylation CYP3A4 (R > S); CYP2B6 (S >> R) CYP3A4 (R > S); CYP2B6 (S >> R) CYP3A4 (R >> S); CYP2B6 (S >> R) [18][19][20][21] ± Fluoxetine N-demethylation CYP2C9 (R >> S) [96] ± Omeprazole Hydroxylation Sulfoxidation 5-O-demethylation CYP2C19 (R >> S) CYP3A4 (S >> R) CYP2C19 (R >> S) [97] ± Mephenytoin 4′-Hydroxylation CYP2C19 (S >> R) [93] ± Disopyramde N-Dealkylation CYP3A4 (S > R); CYP3A5 (S > R) [98] (R)-bufuralol 1′′-Hydroxylation ‡ CYP2D6 (S > R) [99] ± Metoprolol O-Demethylation CYP2D6 (R > S) [100][101][102] ± Verapamil N-demethylation N-dealkylation [46,103,104] ± Cibenzoline p-Hydroxylation CYP2D6 (R >> S) [105] Risperidone 9-Hydroxylation ‡ CYP2D6 (S >> R); CYP3A4 (R >> S) [24] ± Propranolol Glucuronidation UGT1A9 (S >> R); UGT1A10 (R >> S) [28] ± Formoterol Glucuronidation UGT (S > R) [29] ± Fenoterol Sulfation P-PST (S > R); M-PST (R > S) [30] ± Albuterol Sulfation M-PST (S >> R) [31,32] ± Isoproterenol Sulfation M-PST (R >> S) [31] ± Ibuprofen Conjugation Acyl-coenzyme A synthetase (R >> S) [33] *Stereoselectivity based on intrinsic clearance or rate of metabolite formation for the enantiomeric metabolites; ">>" defined as the ratio > 5, otherwise as ">". ‡ Product enantioselectivity.…”

Section: Introductionmentioning

confidence: 99%

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Stereoselectivity in drug metabolism

Lü¹

2007

Expert Opinion on Drug Metabolism & Toxicology

124

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Many chiral drugs are used as their racemic mixtures in clinical practice. Two enantiomers of a chiral drug generally differ in pharmacodynamic and/or pharmacokinetic properties as a consequence of the stereoselective interaction with optically active biological macromolecules. Thus, a stereospecific assay to discriminate between enantiomers is required in order to relate plasma concentrations to pharmacological effect of a chiral drug. Stereoselective metabolism of drugs is most commonly the major contributing factor to stereoselectivity in pharmacokinetics. Metabolizing enzymes often display a preference for one enantiomer of a chiral drug over the other, resulting in enantioselectivity. The structural characteristics of enzymes dictate the enantiomeric discrimination associated with the metabolism of chiral drugs. The stereoselectivity can, therefore, be viewed as the physical property characteristic that phenotypes the enzyme. This review provides a comprehensive appraisal of stereochemical aspects of drug metabolism (i.e., enantioselective metabolism and first-pass effect, enzyme-selective inhibition or induction and drug interaction, species differences and polymorphic metabolism).

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Section: Enantioselective Metabolism By Other Enzymesmentioning

confidence: 99%

Section: Enantioselective Metabolism By Other Enzymesmentioning

confidence: 99%

Section: Enantioselective First-pass Metabolism and Oral Bioavailabilitymentioning

confidence: 99%

Section: Enantioselective First-pass Metabolism and Oral Bioavailabilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stereoselectivity in drug metabolism

Lü¹

2007

Expert Opinion on Drug Metabolism & Toxicology

124

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Mechanisms of Drug Metabolism

Foti

Rock

Wienkers

et al. 2012

Encyclopedia of Drug Metabolism and Interactions

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The study of drug metabolism places significant importance on the molecular properties of the substrate and the topography of the enzyme's active site. Mechanisms of drug metabolism focus on the different reactions catalyzed within each family of drug‐metabolizing enzymes as well as the chemistry involved in phase I and II reactions. Concepts explored include enzyme‐catalyzed reaction mechanisms, physicochemical properties of substrate molecules that result in favorable sites of metabolism for a given enzyme, and factors that contribute to the regioselectivity and stereoselectivity observed for phase I and II drug‐metabolizing enzymes.

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