Warfarin isomers

The Separation of Warfarin Isomers on a CYCLOBOND Column Courtesy of ASTEC Inc. 

Warfarin is available as a racemic mixture containing the R(+) and S(-) enantiomers in equal proportions however, the S-isomer is 3 to 6 times more potent as an anticoagulant than the R-isomer. 

The pharmacological action of codeine is increased by induction as this increases demethylation to morphine. Induction by phenobarbital decreases the toxicity of organo-phosphates, but increases that of phosphorothionates. Studies with the drug warfarin have shown that induction by both phenobarbital and 3-methylcholanthrene will change the stereochemistry of the product, as can be seen in Table 5.24. Thus, hydroxylation in the 8-position in the R-isomer is increased 12 times compared with only 4 times with the S-isomer following 3-methylcholanthrene induction. 

An anomeric effect is also shown by the hydroxy group in the dihydropyran ring of the anticoagulant drug warfarin (165 R = Ph). The related trans-methylketal (165 R = Me) exists as the all-staggered half-chair conformation in which the alkoxy group is axial. However, the cis isomer interconverts between the two half-chair conformations (79JOC798). 

Altered warfarin metabolism. CYP2C9-mediated metabolism of the more potent isomer, S-warfarin, may be induced or inhibited. The less potent... 

Nagashima et al. (33) developed a model in which the forcing function was modeled as proportional to the logarithm of the warfarin concentration in plasma. However, Pitsiu et al. (34) subsequently found that a sigmoid E ax model (Equation 19.11) is more suitable for modeling the relationship between plasma concentrations of S-warfarin, the active isomer of warfarin, and inhibition of coagulation factor formation. 

Pharmacokinetics. Warfarin is readily absorbed from the gastrointestinal tract and like all the oral anticoagulants, is more than 90% bound to plasma proteins. Its action is terminated by metabolism in the liver. Warfarin (t/ 36 h) is a racemic mixture of approximately equal amounts of two isomers S (t)/ 35 h) and R 50 h) warfarin, i.e. it is in effect two drugs. S warfarin is four times more potent than R warfarin. Drugs which interact with warfarin affect these isomers differently. 

Parameter Isomer Warfarin Ibuprofen Disopyramide PropranoF Verapamil ... 

When stereoisomers are biotransformed by a variety of pathways, differences in the susceptibility of the separate isomers to these pathways result in stereoselectivity for their metabolite patterns. For example, 5-warfarin is oxidized to form primarily 7-hydroxy-5-warfarin, whereas the R enantiomer predominantly undergoes hydroxylation in the 6-position.f Oxazepam glucuronidation is 3-3.4 times higher for the S isomer compared to the R isomer in man and dogs. Biotransformation may generate an additional chiral center in the drug structure and result in diastereo-meric metabolites with markedly different disposition characteristics. 

The area of clinical pharmacology that first directed attention to the consequences of stereoisomerism on therapeutic and pharmacokinetics was that of drug interactions, particularly those of the anticoagulant warfarin. Not only may drug interactions be stereoselective, but there is a potential for one stereoisomer to alter the pharmacokinetics and pharmacodynamics of the other. A classical example is the interaction with achiral phenylbutazone, which inhibits the metabolism of active 5-warfarin but stimulates the metabolism of the less active R isomer. Other stereoselective drug interactions include the induced elimination of misoni-dazole by phenytoin. Phenytoin enhances the clearance of (4—)-misonidazole by 56%o, which is higher than the increase in clearance of 33%o noted for (—)-misonidazole. 

Another COX-2-selective non-steroidal antiinflammatory drug, rofecoxib, increased plasma concentrations of the biologically less active isomer, R(+) warfarin, which accounted for an approximately 8% increase in INR at steady state in healthy volunteers (33). 

The effect of warfarin is potentiated by metronidazole (43,44). The mechanism is stereoselective inhibition by metronidazole of the metabolism of 5-warfarin, the more potent isomer (43). There is a similar interaction with acenocoumarol (45,46). 

Phenylbutazone displaces warfarin from binding sites on serum albumin, temporarily increasing its effects before the clearance of warfarin increases because of an increase in the unbound fraction (37). If that were the only mechanism, this interaction would not be important. However, phenylbutazone also inhibits the metabolism of 5-warfarin and induces the metabolism of -warfarin (38) the half-life of racemic warfarin is unchanged, but because the S isomer is more potent than the R isomer, the action of warfarin is potentiated (SED-9,144) (36,39). 

See also Aflatoxin Algae Ammonia Asbestos Benzene Hexachloride, Mixed Isomers Brodifacoum Carbamate Pesticides Carbon Monoxide Castor Bean Copper Coumarins DDT (Dichlorodiphenyltrichloroethane) DEET (Diethyltoluamide) Dichlorvos Dieldrin Ethylene Glycol Hydrogen Sulfide Lead Malathion Methane Molybdenum Mushrooms, Coprine Mushrooms, Cyclopeptide Mycotoxins Nitrites Oleander Organochlorine Insecticides Organophosphates Paraquat Parathion Pyrethrins/Pyrethroids Selenium Sodium Strychnine Sulfur Dioxide Thallium Warfarin. 

Drug metabolism may be influenced by stereochemical factors if the molecule in question possesses one or more chiral centres. Examples of drugs that show stereochemical differences in rates of metabolism include a-methyldopa (where the (S) isomer is decarboxylated more rapidly than the (R) isomer) and the enantiomers of warfarin, which are reduced at different rates. The well-known endogenous compound mevalonic acid (3,5-dihydroxy-3-methylpentanoic acid) is chiral and exists as two enantiomers. When a racemic mixture of mevalonic acid is fed to animals, one optical isomer is absorbed and metabolised, while virtually all of the other isomer is excreted by the kidneys into the urine. 

Many drug compounds are racemic mixtures of stereoisomers. In most cases, one of the isomers is more pharmacologically active than the other isomer, and each isomer may exhibit different pharmacokinetic properties. Warfarin, propranolol, verapamil, and ibuprofen are aU racemic mixtures of stereoisomers. Some drug interactions inhibit or increase the elimination of only one stereoisomer. The importance of the drug interaction depends on which isomer is affected. Other drugs, such as dextromethorphan, levofloxacin, and dUtiazem, are composed of just one stereoisomer. 

SOLBAR (7727-43-7) see barium sulfate. SOLFARIN (81-81-2) see warfarin. SOLFO BLACK B , SOLFO BLACK 2B SUPRA SOLFO BLACK BB , SOLFO BLACK G , SOLFO BLACK SB (51 -28-5) see dinitrophenols, single or mixed isomers. 

The anticoagulant effects of warfarin are stereoselective the S-isomer of warfarin is 3 to 5 times more potent than the R-isomer. 

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