relation between pharmacokinetics and stereochemistry

1. Stereospecific
pharmacokinetics and
pharmacodynamics of
stereoisomeric drugs
Sazan Jameel Haji Ali
Msc. Student / pharmaceutical chemistry
department
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2.  What is Stereochemistry and
stereoisomerism??
 What is the relation between
stereoisomers and
pharmacokinetics??
 How stereoisomers possess different
biological activities ??
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3. • 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.
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4. Terms for non-superimposable
images:
 Optical isomers
 Optical antipodes
 Enantiomers
Identical physical/chemical properties
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5. 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

6. Pharmacokinetics
stereoselectivty
Absorption
• 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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7. Absorption and stereoselectivity
• Passive intestinal absorption
For 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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8. 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.
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9.  Highly albumin bound
 Less potent
 Highly metabolised
 Low plasma
concentration
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• highly bound to AAG
available as unbound
• 40-100 time more
potent
• Less metabolized
• High plasma
concentration.

10. 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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11. o Phase I and phase II metabolism
The magnitude of stereoselectivity depends on the metabolic
pathways involved drug metabolism.
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12. 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
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13. 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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14. Pharmacodynamics
differences
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15.  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 15

16. Quantitative difference
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17. Qualitative difference
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