2. • A carbon atom to which four different groups is
attached is asymmetric or chiral.
3. The two resulting isomers, termed optical isomers or
enantiomers, are mirror images of each other and
have identical physical characteristics.
4.
5. • Molecules having more than one asymmetric center
but which are not mirror images of each other are te
rmed
diastereoisomers and are physically different.
• Solutions of enantiomers rotate polarized light. An
enantiomer which rotates light to the right is
dextrorotatory, abbreviated as d or (+).
• The other enantiomer will rotate the light to the left
by
the same absolute magnitude and is laevorotatory,
abbreviation I or (-).
• A racemate is an equal mixture of the enantiomers
and does not rotate polarized light.
6.
7. • Chirality and drug development
In pharmaceutical industries:
56% of the drugs currently in use are chiral molecules and
88% of the last ones are marketed as racemates, consisting of
an equi molar mixture of two enantiomers.
8. Although the enantiomers of chiral drugs have the same
chemical connectivity of atoms.
they exhibit marked differences in their pharmacology,
toxicology, pharmacokinetics, metabolism etc.
when chiral drugs are synthesized, as much effort goes
towards the rigorous separation of the two enantiomers.
This ensures that only the biologically active enantiomer is
present in the final drug preparation.
9. The enantiomers of a chiral drug differ in their interactions
with enzymes, proteins, receptors and other chiral molecules
too including chiral catalysts.
These differences in interactions, in turn, lead to differences
in the biological activities of the two enantiomers, such as
their pharmacology, pharmacokinetics, metabolism, toxicity,
immune response etc.
*Surprisingly, biological systems can recognize the two
enantiomers as two very different substances. *
10.
11. 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
13. 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.
14. there was a 15% difference in the bioavailability of the
enantiomers of atenolol, Although it was postulated that
this was a result of an enantioselective active absorption.
Pharmacokinetic differences resulting out of :
stereoisomerism can be in absorption like L-Methotrexate is
better absorbed than D-Methotrexate.
Esomeprazole is more bioavailable than racemic
omeprazole.
15. Active transport, which involves recognition of the
enantiomers by the carrier protein, may be expected to
demonstrate enantioselectivity
L dopa, methotrexate and folinic acid. It may be expected,
however, that unless there is some natural restrict ion to
passive absorption, such enantioselectivity would affect only
the rate, and not the extent, of absorption.
although levodopa(L-dopa) is absorbed much more
rapidly than D-dopa, they are both absorbed to the same
extent.
16. distribution
Stereoselectivity in drug distribution may occur as a
result of binding to either plasma or tissue proteins and
transport via specific tissue uptake and storage mechanisms
The majority of drugs bind in a reversible manner to
plasma proteins, notably to human serum albumin (HSA)
and/or a1-acid glycoprotein (AGP).
Acidic drugs bind preferentially to HSA
basic drugs predominantely bind to AGP.
17. • 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
the R-propranolol binding to albumin is greater than
S-propranolol .
the opposite is observed for 1 -acid glycoprotein.
18. S-Warfarin is more extensively bound to albumin
than R-Warfarin, hence it has lower volume of
distribution.
Levocetrizine has smaller volume of distribution
than its dextroisomer .
d-Propranolol is more extensively bound to proteins
than l-Propranolol.
19. • Highly albumin bound
• Less potent
• Highly metabolised
• Low plasma concentration
• highly bound to AAG
available as unbound
• 40-100 time more potent
• Less metabolized
• High plasma
concentration
20. Protein binding
• Particularly large differences in protein binding affinities
have been observed between benzodiazepine enantiomers;
up to 35-fold for oxazepam hemisuccinate.
• Differences are generally much smaller, but for highly
bound drugs these differences may account for significant
differences in total renal clearance and total body clearance.
• For disopyramide, enantioselective and concentration
dependent protein binding account for the stereoselective
differences in renal clearance of the enantiomers following
administration of the racemic drug.
21. distribution
• Also of interest is the enantioselective protein binding
interaction reported between warfarin and lorazepam acetate.
• R,S-warfarin allosterically increased the binding of
S-lorazepam acetate but there was no effect on them
R-enantiomer.
• Similarly, S-lorazepam acetate increased the binding of
R,S-warfarin
22. o many antiarrhythmic drugs are marketed as racemates such
as disopyramide, encainide, flecainide, mexiletine, propafe
none, tocainide, etc.
o The absorption of chiral antiarrhythmics appears to be
nonstereoselective. However, their distribution,
metabolism and renal excretion usually favour one
enantiomer versus the other. In terms of distribution,
o plasma protein binding is stereoselective for most of
these drugs, resulting in up to two-fold differences
between the enantiomers in their unbound fractions in
plasma and volume of distribution.
23.
24. • It is noteworthy that stereoselectivity in binding may
vary for different proteins, e.g., the protein binding of
propranolol to AGP is stereoselective for the
S-enantiomer, whereas binding to HSA favors
(R)-propranolol.
• In whole plasma the binding to AGP is dominant so
that the free fraction of the R-enantiomer is greater
than that of (S)-propranolol.
25. • Enantioselective tissue uptake, which is in part a
consequence of enantioselective plasma protein binding, has
been reported.
• For example, the transport of ibuprofen into both synovial
and blister fluids is preferential for the S-enantiomer owing
to the higher free fraction of this enantiomer in plasma.
• In addition, the affinity of stereoisomers for binding sites
in specific tissues may also differ and contribute to
stereoselective tissue binding, e.g., (S)-leucovorin accumulates in
tumor cells in vitro to a greater degree than the R-enantiomer.
26. • The uptake of ibuprofen into lipids is stereoselective in
favor of the R-enantiomer.
28. References:
1-Reddy, Indra K., and Reza Mehvar, eds. Chirality in drug design
and development. CRC Press, 2004.
2-McConathy, Jonathan, and Michael J. Owens. "Stereochemistry
in drug action." Primary care companion to the Journal of clinical
psychiatry 5.2 (2003): 70.
3-Lin, Guo‐Qiang, Jian‐Ge Zhang, and Jie‐Fei Cheng. "Overview
of chirality and chiral drugs." Chiral Drugs: Chemistry and Biolog
ical Action (2011): 14-18.
4-Nguyen, Lien Ai, Hua He, and Chuong Pham-Huy. "Chiral drug
s: an overview." Int J Biomed Sci 2.2 (2006): 85-100.
5-Lee, Edmund JD, and Ken M. Williams. "Chirality clinical phar
macokinetic and pharmacodynamic considerations." Clinical phar
macokinetics 18.5 (1990): 339-345.
