Racemic drugs biotransformation

Similar to many other cases of biologically active compounds, stereochemistry influences the pharmacological effect of a chiral drug. This can be explained by the fact that there is only one energeticaUy favorable (specific) interaction of an active molecule with its receptor, both being chiral structures. Qualitative and quantitative differences are caused by different receptor affinities as demonstrated in Fig, 1 (1). The metabolism (biotransformation) of drugs is mainly caused by enzymes, which are chiral macromolecules and discriminate between substrate molecules of different stereochemistry, This may result in metabolites of different activity and in different pharmacokinetics, resorption, and excretion. Therefore, racemic drugs should be looked on as a 1 1 mixture of two different compounds. 

The 4- and 5-hydroxylated metabolites of (R)- or (S)-propranolol were produced by biotransformation with two fungal strains, starting from either the racemic drug or pure enantiomers. The strain M50036 operated a... 

Another, commonly known example of stereoselective drug biotransformation is in vitro and in vivo conversion of inactive ( )-(—)-ibuprofen to the active (5)-(-l-)-enantiomer in drug formulations containing ibuprofen racemate [30-32]. 

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... 

One of the most important advantages of biocatalysts is their stereospedficity. An example of a stereospedfic biotransformation is given in Figure 2.3. In 1992 the Food and Drug Administration (FDA) in the United States addressed the issue of whether it mattered, for drug approval purposes, that a preparation of a synthetic chiral molecule (one or more as)rmmetric centers) contains not one but two compounds (racemates) -the two mirror-image stereoisomers (individual enantiomers). 

Because of biotransformations after the drug is administered, it sometimes makes little difference whether a racemic mixture or one isomer is administered. The popular nonsteroidal anti-inflammatory drug (NSAID) ibuprofen is sold as... 

Pearce, R.E., Gotschall, R.R., Kearns, G.L. and Leeder, J.S. (2001) Cytochrome P-450 involvement in the biotransformation of cisapride and racemic nordsapride in vitro differential activity of individual human CYP3A isoforms. Drug Metabolism and Disposition The Biological Fate of Chemicals, 29, 1548-1554. 

Some chiral drugs available as racemates may interact with other drugs in such a way that biotransformation of only one enantiomer would be hindered. This may lead to major differences in the pharmacological potency and higher... 

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