The document discusses key concepts regarding enantiomers including: 1. Enantiomers are chiral molecules that are non-superimposable mirror images of one another that rotate plane-polarized light in opposite directions. 2. Diastereomers have more than one asymmetric carbon center and are physically different. 3. Differences in interactions between enantiomers and biological systems can lead to differences in pharmacological effects. 4. Stereoselectivity can occur during the absorption, distribution, metabolism, and excretion of chiral drugs due to interactions with transporters, proteins, and enzymes. 5. Case studies provide specific examples of how stereoselectivity influences the pharmacokinetics of drug enantiomers

1. PRESENTED BY: ROHIT PAL
M PHARMA FIRST YEAR
PHARMACEUTICAL CHEMISTRY

2.  A carbon atom to which four different groups are attached is chiral.
 Enantiomers are chiral molecules that are mirror images of one another.
Furthermore, the molecules are non-superimposable on one another.
This means that the molecules cannot be placed on top of one another
and give the same molecule.

3.  Enantiomers differ in the direction that they
rotate plane polarized light.
 S-enantiomer = anticlockwise
 R-enantiomer = clockwise

4.  Molecules having more than one asymmetric
centre but which are not mirror images of
each other are termed 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, abbreviated as I or (-).
 A racemate is an equal mixture of the
enantiomers and does not rotate polarized
light.

5.  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.

8.  Absorption
• Passive intestinal absorption
• Carrier transporter stereoselectivity
 Distribution
• Protein binding
• Tissue distribution
 Metabolism
• first pass metabolism
• Phase I and phase II metabolism
 Elimination

9.  Passive intestinal absorption: For majority of
racemic drugs, absorption appears to be by
passive diffusion, provided no
stereoselectivity.

10.  Carrier mediated transporter: Stereo selective
intestinal transporter is the main cause for
marked difference in the oral absorption of
enantiomers.
L- Methotrexate have 40 fold higher Cmax and
AUC than D- Methotrexate

11.  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.
 Active transport, which involves recognition of
the enantiomers by the carrier protein, may be
expected to demonstrate enantioselectivity.

12.  Although levodopa(L-dopa) is absorbed much
more rapidly than D-dopa, they are both
absorbed to the same extent.
L-dopa D-dopa

13.  Stereo selectivity 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 α-acid
glycoprotein(AGP).
 Acidic drugs bind preferentially to HAS and
basic drugs predominantely bind to AGP.

14.  Stereoselective plasma protein binding could
influence distribution and elimination because the
major determinant of drug distribution and
elimination is protein binding.

15.  The free fraction of R-enantiomer of propranolol is
greater than that of S-enantiomer of propranolol.
 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 α1 – acid glycoprotein.
 S-Warfarin is more extensively bound to albumin
than R-Warfarin, hence it has lower volume of
distribution.

16. R-propanolol S-propanolol

17.  Levocetrizine has smaller volume of distribution than
its dextroisomer .
 There is enantio selective protein binding interaction
reported b/w warfarin & 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.

18.  Enantio selective tissue uptake, which is in part a
consequence of enantio selective 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 stereo selective tissue binding
Eg :- S-leucovorin accumulates in tumor cell invitro to
a greater degree than the R enantiomer

19.  stereoselectivity in metabolism is probably
responsible for the majority of the differences
observed in enantioselective drug disposition .
 Stereoselectivity in metabolism may arise from
differences in the binding of enantiomeric
substrates to the enzyme active site and/or be
associated with catalysis owing to differential
reactivity and orientation of the target groups to
the catalytic site .
 As a result, pair of enantiomers is frequently
metabolized at different rates and/or via
different routes to yield alternative products.

21.  The stereoselectivity of the reactions of drug
metabolism may be classified into three
groups in terms of their selectivity with
respect to the substrate, the product, or both.
substrate selectivity - one enantiomer is
metabolized more rapidly than the other .
product stereoselectivity - in which one
particular stereoisomer of a metabolite is
produced preferentially
substrate– product stereoselectivity - where one
enantiomer is preferentially metabolized to
yield a particular diastereoisomeric product

22.  Using this approach, metabolic pathways may
be divided into five groups.
Prochiral to chiral transformations
Chiral to chiral transformations
Chiral to diastereoisomer transformations
Chiral to achiral transformations
Chiral inversion

23.  Prochiral to chiral transformations
Metabolism taking place either at a prochiral
center or on an enantiotopic group within the
molecule.
1. For example, The prochiral sulphide
cimetidine undergoes sulphoxidation to yield
the corresponding sulphoxide, the
enantiomeric composition.

24. 2. Phenytoin undergoes Stereoselective para-
hydroxylation to yield (S)-4’-hydroxyphenytoin,
which is greater i.e. 90% than other enantiomer.

25.  Chiral to chiral transformations
The individual enantiomers of a drug undergo
metabolism at a site remote from the centre of
chirality with no configurational consequences.
For example
(S)-warfarin undergoes aromatic oxidation
mediated by CYP 2C9 in the 7- and 6-positions
to yield (S)-7-hydroxy- and (S)-6-
hydroxywarfarin in the ratio 3.5: 1.

26.  Chiral to diastereoisomer transformations
A second chiral centre is introduced into the
drug either by reaction at a prochiral centre or
via conjugation with a chiral conjugating agent.
Eg;- aliphatic oxidation of pentobarbitone and
the keto- reduction of warfarin to yield the
corresponding diastereoisomeric alcohol
derivatives or the stereoselective
glucuronidation of oxazepam.

27. Chiral to achiral transformations :
The substrate undergoes metabolism at the center of
chirality, resulting in a loss of asymmetry.
Examples
Aromatization of the dihydropyridine calcium channel
blocking agents, e.g., Nilvadipine, to yield the
corresponding pyridine derivative.

28. Examples
Omperazole, which undergoes CYP 3A4–mediated oxidation
at the chiral sulphoxide to yield the corresponding sulphone.
the reaction shows tenfold selectivity for the S-enantiomer
in terms of intrinsic clearance.

29. Chiral inversion:
one stereoisomer is metabolically converted into its
enantiomer with no other alteration in structure.
Agents undergoing this type of transformations
 2-aryl propionic acid (2-APAs)
 NSAIDS (eg;ibuprofen, fenoprofen, flurbiprofen,
ketoprofen)
 2-aryloxypropionic acid herbicide (eg;haloxyfop)
 In the case of the 2-APAs, the reaction is essentially
stereospecific, the less active, or inactive, R-
enantiomers undergoing inversion to the active S-
enantiomers.

30. Machanism

31. Verapamil:
(S)-Verapamil being 10 to 20 times more potent than its antipode.
(S)-verapamil has been shown to be preferentially metabolized
following oral administration, thereby leading to the predominance
of (R)-isomer in plasma.
The differences between the plasma concentrations of two
enantiomers were much more pronounced after oral administration
compared with intravenous administration. Greater than two fold
higher Cmax and AUC values of (R)-verapamil was due to a more
than two fold difference in the presystemic metabolism of two
enantiomers in favor of (S)-verapamil.

32. RENAL EXCRETION
 Stereo selectivity in renal clearance may arise as a
result of either selectivity in protein binding,
influencing glomerular filtration and passive
reabsorption, or active secretion or reabsorption.
 Enantio selectivity in renal clearance with
enantiomeric ratios between 1.0 and 3.0
 In the case of the diastereoisomers quinine and
quinidine –clearance is about 24.7 and 99 mLmin-1
respectively.

33.  For those agents that undergo active tubular
secretion, interactions between enantiomers may
occur such that their excretion differs following
administration as single enantiomers versus the
racemat.
EXAMPLE:-1
 Administration of the quinolone antimicrobial
agent (S)- ofloxacin with increasing amounts of the
R-enantiomer to the cynomolgus monkey which
results in a reduction in both the total and the
renal clearance of the S-enantiomer.
MECHANISM:-
 By competitive inhibition of transport mechanism
(organic cation transport system)

34. EXAMPLE:-2
 In case of pindolol, tubular secretion of (S)-
enantiomer being 30% greater than that of (R)-
enantiomer.
 Both the renal and the tubular secretion clearance of
both enantiomers is inhibited by cimetidine,
presumably by inhibition of the renal organic cation
transport system.
 The renal clearance of (S) - pindolol, the enantiomer
with the greater renal and the tubular secretion
clearance, was reduced to a smaller extent (26%) than
that of the R-enantiomer (34%)
 It indicate that the secretion of the drug is mediated
by more than one transporter, and that cimetidine
has differential inhibitory properties.

35. (±)-Pindolol Enantiomers

37. Case Study 1.
Wade et a1 reported that the absorption of dopa
from rat small intestine was an active process which
favoured the L-enantiomer.
It was later noted that D-dopa is also absorbed, but
by passive diffusion. The active absorption of
methotrexate also favors the L-enantiomer.
Chiral β-lactam antibiotics are actively absorbed via
the dipeptide transport system which is present in
the intestinal brush border membrane.

38. Case Study 2.
 The mechanism of absorption, the rate may also influence the
pharmacokinetics of drug enantiomers. Ibuprofen, a 2-
arylpropionic acid (2-APA) nonsteroidal antiinflammatory drug
(NSAID), is administered as a racemate.
 The therapeutically “inactive” R-enantiomer, however, undergoes
a unidirectional metabolic inversion to the active antipode.
 It has been proposed that in humans the inversion, and
consequently the concentration of the active enantiomer, is
influenced by the rate of absorption.
 Inversion appears to take place presystemically in the GI tract;
hence, the longer a dose resides there, the greater will be the
extent of inversion.
 Indeed, a significant positive correlation between the time to
peak plasma ibuprofen concentration and the S:R concentration
ratios has been observed.
 The absorption rate dependancy of ibuprofen enantiomeric
inversion becomes more evident after careful examination of a
more recent set of data (i.e., greater S:R AUC ratios in subjects
with longer time to peak concentration).
 Similarly, greater S:R AUC concentration ratios have recently
been reported for sustained-release oral formulations of
ibuprofen.

39. Case Study 3
 In six healthy japanese subjects given 30mg
of racemate, marked stereoslectivity was
found in the pharmocokinects of
lansoprazole.
 The mean Cmax and AUC ratio of R(+):S(-)
lansoprazole were 2.9 and 4.5 respectively.
 The elimination t1/2 of enantiomer were
similar, but a 4-8 folds larger Vd/F was
determined for S(-) enantiomer.
 The two folds higher unbound fraction of S(-)
in plasma explain its higher Vd/F.

40. Case study 4:
 Gossypol is a naturally occurring compound that is
administrated as the racemate consisting of two geometric
stereoisomers, which has been examined for its utility as
a male antifertility drug.
 The pharmacokinetics of gossypol have been examined in
healthy men after administration of either 20mg racemate
or 20mg of (+) or (-) enantiomer separately.
 The assay was carried out the mean ratio of (+): (-) AUC
and half life ratio were 4.8 and 29 respectively.
 The reason behind, (-) enantiomer is pharmacologically
active.
 There is minimal accumulation would occur for (-)
enantiomer on repeated doses.
 It would also follow that with repeated dosing significant
accumulation of the (+) enantiomer would occur in plasma
 Gossypol has more recently been proposed for use as an
anticancer agent, with (-) enantiomer displaying of greater
cytotoxic potential to tumour cell culture than (+)
gossypol.

41. Case Study 5:
 The (+) enantiomer of propranolol is largely
devoid of β- blocking activity.
 The study on propranolol, has been found to
show effective an anti-fertility action.
 When used topically in combination with
nonoxynol-9 sperm motility was significantly
reduced as compare to use of nonoxynol-9
alone.
 The basis of the effect was thought to be due to
membrane stabilizing effect of propranolol which
is shared between two enantiomers.