stereoselectivity in pharmacokinetics

1. Pharmacokinetics
stereoselectivity
PRESENTED BY: SWAFVAN K
M PHARM FIRST YEAR
PHARMACEUTICAL CHEMISTRY

2. Pharmacokinetics stereoselectivity
Absorption
•Passive intestinal absorption
•Carrier transporter stereoselectivity
Distribution
•Protein binding
•Tissue distribution
Metabolism
•First pass metabolism
•Phase 1 and Phase2 metabolism
Elimination

3. Absorption and stereoselectivity
• Passive intestinal absorption:
For majority of racemic drugs, absorption
appears to be by passive diffusion, provided no
stereoselectivity.
• 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

4. Absorption and stereoselectivity
 There was 15% difference in bioavailability of the
enantiomers of atenolol, Although it was postulated
that this was a result of an enantio selective active
absorption.
 Esomeprazole is more bioavailable than racemic
omeprazole.
 In case of L-dopa & methotrexate, enantioselectivity
would affect only the rate and not to the extent, of
absorption.
 Although L-dopa is absorbed much more rapidly than
D-dopa, they are both absorbed to the same extent.

5. DISTRIBUTION
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).

6. DISTRIBUTION
 The enantiomers may display different magnitudes of
stereoselectivity b/w the various proteins found in plasma.
Eg :- The R-propanolol binding to albumin is greater than S-
propanolol. 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.
 Levocetrizin has smaller volume distribution than its dextro
isomer
 d-propanolol more extensively bound to proteins than l-
propanolol

7. DISTRIBUTION
R-propanolol
• Highly albumin bound
• Less potent
• Highly metabolized
• Low plasma concentration
S-propanolol
• Highly bound to AAG available
as unbound.
• 40-100 time more potent.
• Less metabolized.
• Highly plasma concentration.

8. DISTRIBUTION
• 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.

9. DISTRIBUTION
 Many antiarrythmic drugs are marketed as racemates
such as disopyramide, encainide, flecainide,
mexiletine, propafenone, tocainide etc
 Plasma protein binding is stereo selective for most of
the drugs, resulting in up to two fold differences b/w
the enantiomers in their unbound fraction in plasma &
volume of distribution.

10. DISTRIBUTION
 Enantio selective tissue uptake, whis 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

11. METABOLISM
 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.

12. METABOLISM
 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

13. METABOLISM
 An alternative classification involves the
stereochemical consequences of the transformation
reaction. 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

14. METABOLISM
Prochiral to chiral transformations
• metabolism taking place either at a prochiral
center or on an enantiotopic group within the
molecule.
For example,
The prochiral sulphide cimetidine undergoes
sulphoxidation to yield the corresponding
sulphoxide, the enantiomeric composition

15. METABOLISM
Prochiral to chiral transformations
For example,
1- The prochiral sulphide cimetidine undergoes
sulphoxidation to yield the corresponding sulphoxide,
the enantiomeric composition

16. METABOLISM
Prochiral to chiral transformations
For example,
2- Phenytoin undergoes stereoselective para- hydroxylation to
yield (S)-4’-hydroxyphenytoin in greater than 90% enantiomeric
excess following drug administration to man

17. METABOLISM
 Chiral to chiral transformations :
the individual enantiomers of a drug undergo metabolism at
a site remote from the center 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.

18. METABOLISM
 Chiral to diastereoisomer transformations:
a second chiral center is introduced into the drug either by
reaction at a prochiral center 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.

19. METABOLISM
 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

20. METABOLISM
 Chiral to achiral transformations :
Examples
 the oxidation of the benzimidazole proton pump inhibitors, e.g.,
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.

21. METABOLISM
 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)

22. METABOLISM
 Chiral inversion:
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
Mechanism

23. METABOLISM
Stiripentol
 following oral administration of one enantiomer, it
undergoes acid catalysed racemization & both enantimers
are formed
In case of (S)-enantiomer- only minor quantities of (R)-
enantiomer could be detected because of glucoronidation
of (R)-enanatiomer in liver

24. METABOLISM
Flosiquinan
Following administration of either enantiomer of
flosiquinan,alternative enantiomer could be detected in
plasma.
(R)-enantiomer – AUC approximately 8% for (S)-enantiomer
(S)-enantiomer – AUC approximately 25 for (R)-enantiomer

25. 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 and99 mLmin-1 respectively.

26. RENAL EXCRETION
 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 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)

27. RENAL EXCRETION
EXAMPLE:-2
Differences in the total and the renal clearance of the
enantiomers of the uricosuric diuretic 5-dimethyl sulphamoyl-
6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (DBCA).
Administration of the racemic drug to the monkey results in a
25% reduction in the total and the renal clearance, and a 30%
reduction in the tubular secretion clearance, of the
S-enantiomer in comparison to the values obtained following
administration of the single enantiomer
 corresponding reductions in the same parameters for (R)-DBCA
did not achieve statistical significance.

28. RENAL EXCRETION
EXAMPLE:-3
Coadministration of the racemic drug with probenecid
resulted in significant reductions in the tubular secretion of
both enantiomers but was stereoselective for (S)-DBCA, the
decrease in clearance being 53% and 14% for the S- and R-
enantiomers, respectively.

29. RENAL EXCRETION
EXAMPLE:-4
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.

30. THANK YOU!