Stereospecific

pharmacokinetics and

pharmacodynamics of

stereoisomeric drugs

Sazan Jameel Haji Ali

Msc. Student / pharmaceutical chemistry

department

1

What is Stereochemistry and

stereoisomerism??

What is the relation between

stereoisomers and

pharmacokinetics??

How stereoisomers possess different

biological activities ??

2

• Stereochemistry : A sub discipline of chemistry,

concerned with three dimensional spatial arrangement

of the atoms within a molecule.

• Stereoisomers : Compounds with the same

molecular connectivity but differ in the spatial

arrangement of their constituent atoms or groups.

• Enantiomers : Stereoisomers with non

superimposable mirror images.

• Diastereomers : Stereoisomers which are not

enantiomers.

3

Terms for non-superimposable

images:

Optical isomers

Optical antipodes

Enantiomers

Identical physical/chemical properties

4

Many drugs used in clinical practice

contain one or more chiral centers. These

chiral drugs are often used

therapeutically either as pure

stereoisomers or as a racemic mixture.

The three dimensional interaction of two

enantiomers with a macromolecule, such

as an enzyme or receptor, to form

diastereomeric complexes may result in

chiral recognition and significant

differences in pharmacokinetic

processes as well as the

pharmacodynamics. 5

Pharmacokinetics

stereoselectivtyAbsorption

• Passive intestinal absorption

• Carrier transporter stereoselectivity

Distribution• Protein binding

• Tissue distribution

Metabolism • first pass metabolism

• Phase I and phase II metabolism

Elimination

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Absorption and stereoselectivity

• Passive intestinal absorptionFor the majority of racemic drugs, absorption

appears to be by passive diffusion , provided no

stereoselectivity.

• Carrier mediated transporter Stereoselective intestinal transporter is the main

cause for marked differences in the oral absorption

of enantiomers.

L-methotrexate have 40 fold higher Cmax and AUC

than D-methotrxate.

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Distribution

Protein binding Stereoselective plasma protein binding could

influence distribution and elimination because the

major determinant of drug distribution and

elimination is protein binding.

The enantiomers may display different magnitudes of

stereoselectivity between the various proteins found

in plasma

Ex// the R-propranolol binding to albumin is greater

than S-propranolol and the opposite is observed for

1 -acid glycoprotein.

8

Highly albumin bound

Less potent

Highly metabolised

Low plasma

concentration

9

• highly bound to AAG

available as unbound

• 40-100 time more

potent

• Less metabolized

• High plasma

concentration.

Metabolism

Stereoselective drug metabolism is commonly

observed in vitro for racemic drugs and can

results in substantial differences in the vivo

plasma concentration –time profiles between

enantiomers due to stereoselective

bioavailability or drug disposition.

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o Phase I and phase II metabolismThe magnitude of stereoselectivity depends on the metabolic

pathways involved drug metabolism.

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some time the two isomers compete with each other

to bind the enzyme binding site, this result in

inhibition the metabolism of the one enantiomer.

Ex//propaphenon

12

First pass metabolism and

bioavailability

For low extraction drugs ,stereoselectivity will

directly impact Clh and result in difference in

the enantiomeric Cp after both oral and IV

dosing.

For highly extracted chiral drug stereselective

intrinsic clearance may not alter enantiomer

Cp.

(R)-verapamil have two fold higher Cmax and AUC

than (S)-enantiomer.

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Pharmacodynamics

differences

14

Enantiomers have identical efficacy and toxicity.

Enantiomers may have the same therapeutic and toxic effects, but differ in magnitude.

One enantiomer may possess virtually all the pharmacological activity while the other is essentially biologically inactive.

Both enantiomers may be pharmacologically active but have qualitatively different therapeutic and toxic effects.

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Quantitative difference

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Qualitative difference

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