Stereochemistry metabolism, effects

Minor changes in the stereochemistry and substitution pattern of the steran skeleton result in vastly different yet specific physiological and pharmacological effects, which in turn influence developmental, metabolic, and behavioral phenomena. The organic chemistry and biochemistry of steroids is the subject of many excellent books and an enormous amount of research and patent literature. This chapter compares and contrasts the structure and mode of action of various steroids, their role in regulating hormonal secretion, and the timing of this regulatory action. 

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 cis effect can also determine the stereochemistry of enzymatic reactions. The most prominent example is the metabolism of toxic fluoroacetate in the Krebs... 

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. 

The effect of ring A-hydroxy stereochemistry on in vivo activity has not yet been investigated in great detail. The l(S-OH-D3 analog is reported to be inactive a finding in accord with the very low affinity of this compound for the receptor protein in intestine The absence of the 3jS-OH-function reduces in vivo activity, but not dramatically 3-deoxy-la,25-(OH)2D3 is estimated to approximate the potency of la,25-(OH)2D3 ) and S-deoxy-la-OH-Ds is 20—50 times less active than la-OH-D3, a result that again implies metabolic conversion (to 3-deoxy-la,25-(0H)2D3) since 3-deoxy-la-OH-D3 hself exhibits either low (receptor binding) or no (bone resorption) activity in vitro K... 

The role of the skin as a portal of entry for chiral molecules is becoming an increasingly active and exciting field of research. To date, however, only a few investigations have been focused on the effect of enantiomeric differences of chiral drugs with respect to binding or metabolism in the skin on their transdermal delivery. There may be several sources for any observed enantioselectivity in terms of skin permeation of chiral drugs. For example, the components of the stratum corneum such as keratin and ceramides can serve as sources for chiral discrimination that could result in differential diffusion rates, dependent upon the stereochemistry of the solute. 

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