PHARMACOKINETICS AND BIOPHARMACEUTICS (46:138)

LECTURE TUTORIAL

Stereochemistry Considerations

 

Key Terms:

 

Chiral carbon: A carbon atom that have 4 different ligands, which makes the molecule asymmetric.

 

Optical isomers, optical isomers, enantiomers: Terms used to refer to non-superimposable images. Optical isomers have identical chemical properties (melting point, solubility, etc.). They differ only by their geometric configuration. In other words, the only difference between such compounds is spatial.

 

Racemic mixture: A chemical mixture of enantiomers.

 

Diastereomers: Compounds that possess more than one chiral center. Inversion of 1 chiral center produces a compound that is not the mirror image of the other compound. Importantly, diastereomers may have different chemical properties (solubility, melting point, etc). This means that it is easier to separate diastereomers into their pure form than enantiomers.

 

Epimerization: The formation of diastereomers. This will sometimes occur when a solid drug is solubilized.

 

Key Principles:

 

            Because the spatial configuration of diastereomers and enantiomers differ, they may differ in their affinity for macromolecules important in pharmacodynamic and pharmacokinetic processes. This means that any kinetic or dynamic process that requires interaction with a macromolecule has the potential to exhibit stereoselectivity. Indeed, demonstration of stereoselectivity in a process is evidence that it involves the interaction with a macromolecule. For example, if a compound displays stereoselective absorption, that is evidence that it is likely absorbed by a carrier-mediated process. If absorption were passive, there should be no difference between the enantiomers, since they are chemically identical.

 

            Not all enantiomers display stereoselectivity. Whether or not stereoselectivity will be seen with a dynamic or kinetic process depends upon 2 things: 1) if the chiral center is the portion of the molecule that acts within the binding site and 2) if the requirements for binding to the macromolecule are stringent enough that the difference in spatial configuration alters the affinity of binding. Hence, when considering the comparison of pharmacodynamics between enantiomers, all the following are possible:

 

·        Enantiomers may have identical efficacy and toxicity

·        Enantiomers may have the same effects qualitatively, but differ in the magnitude of effect

·        Enantiomers may differ in their effects qualitatively (i.e., possess different actions)

·        One enantiomers may possess all the pharmacologic effect and the other be essentially inactive

 

Use of a non-stereoselective assay for a drug administered as a racemic mixture may result in erroneous conclusions about the pharmacokinetics of a drug. Most quantitative assays for drugs in biological fluids are not stereoselective. If there are significant differences in the pharmacologic effects of the optical isomers, it a stereoselective assay may be necessary for optimal development of dosage regimens. For example, consider the case of a drug administered as a racemic mixture for which the l-isomer is inactive and the d-isomer possess potent analgesic activity. Furthermore, assume both isomers are eliminated by hepatic metabolism, with half-lives of 12 and 8 hrs for the l- and d-isomers, respectively. Based on analysis of drug concentrations using a non-stereoselective assay, one would determine that the drug had a half-life of 12 hrs and recommend a dosing interval of 12 hr. This may result in the concentrations of the active isomer falling to levels below that which is active (since the half-life of the active isomer is only 8 hrs). On the other hand, with a stereoselective assay one would be able to accurately determine the pharmacokinetics of the active isomer and develop more appropriate dosage regimens.

 

Practice Problems:

 

1.      Mexilitine is an antiarrhythmic agent that is marketed as a racemic mixture. Studies in man have demonstrated that the drug exhibits a volume of distribution that differs between the two isomers. Provide a plausible explanation for this observation.  Answer

 

2.      XT4589 is an experimental anticonvulsant that is optically active. Stereospecific synthesis has been difficult to accomplish with a methodology that capable of scale-up to production quantities. Therefore, the manufacturer is considering marketing the drug as a racemic mixture rather than a pure enantiomer. A stereoselective assay has been developed and reveals that the steady-state brain concentration of the l-isomer is approximately equivalent to plasma concentration, while that for the d­-isomer is substantially less than the plasma concentration. Since they are enantiomers, their physicochemical properties (such as lipophilicity) are the same. In vitro studies reveal that the compound does not exhibit stereoselective plasma protein binding. Interestingly, the enantiomers also display different oral bioavailabilities, with the l-isomer have a substantially higher bioavailability Provide a plausible explanation for the observed differences in brain concentration between the two enantiomers of XT4589.  Answer

 

 

Last revised 07/19/05

 

ã 2005 - Craig K. Svensson, Pharm.D., Ph.D.

 

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