sterosekective pharmacokinetics and metabolism of chiral drugs

1. Stereoselective pharmacokinetics
and metabolism of chiral drugs
Present by: khatereh zarkesh PhD student of pharmaceutics in sums

2. Enantiomer
A chiral molecule is non-superimposable on its mirror image, so that the mirror
image is actually a different molecule.* The two non-identical mirror images are
a pair of enantiomers. Unlike other sorts of isomers, enantiomers have identical
physical and chemical propertie.

3. Diastomer
Diastereomers are a type of a stereoisomer. Diastereomerism occurs when
two or more stereoisomers of a compound have different configurations at
one or more of the equivalent stereocenters and are not mirror images of
each other. When two diastereoisomers differ from each other at only one
stereocenter they are epimers.

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

5. Absorption and stereoselectivity
o Passive intestinal absorption NO stereoselectivity
o Carrier mediated transporter:
there was a 15% difference in the bioavailability of the enanliomers of
atenolol.
Active transport, which involves recognition of the enantiomers by the carrier
protein, may be expected to demonstrate enantioselectivity
L dopa(although levodopa is absorbed much more rapidly than D-dopa, they are
both absorbed to the same extent.) L- Methotrexate have 40 fold higher
Cmax and AUC than D- Methotrexate , and folinic acid.

6. 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.
There are two high-affinity binding sites of most drugs to human serum
albumin, the warfarin site (or site I) and the benzodiazepine and indole site
(site 11) Drugs that bind to site II do so in a highly stereoselective manner.

8.  α-acid glycoprotein(AGP)

9. Stereoselectivity in drug 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.

10. 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

11. Chiral to chiral transformations
Investigations of the metabolic stereochemistry of warfarin have
shown that the principal routes of metabolism are aromatic hydroxylation of the
7-position of the coumarin ring and ketone reduction in the side-chain .
The latter route produces a new chiral centre which results in the production of
diastereoisomers. In the cases of warfarin and its analogues, the R-enantiomers
are converted into the (S)-alcohols by two enzymes present in rat liver cytosol.

12. Chiral to diastereoisomeric
metabolites
a second chiral center is introduced into the drug either by reaction at a
prochiral center or via conjugation with a chiral conjugating agent.
aliphatic oxidation of pentobarbitone and the ketoreduction of warfarin to yield
the corresponding diastereoisomeric alcohol derivatives or the stereoselective
glucuronidation of oxazepam.

13. Chiral to non-chiral transformations
Chirality may be lost by oxidative metabolism at a chiral centre, e.g., oxidation
of secondary alcohols to yield ketones , deamination of amphetamine to yield
phenylacetone and oxidative aromatization of the dihydropyridine
calcium channel blocking drugs such as nilvadipine.

14. Prochiral to chiral transformations
The prochiral sulphide cimetidine undergoes sulphoxidation to yield the
corresponding sulphoxide, the enantiomeric composition.

15. Metabolic chiral inversion
Studies on the chiral inversion reaction have mainly involved the 2-arylpropionic
acid (the "profens") non-steroidal anti-inflammatory drugs (NSAIDs) .
These agents possess a chiral centre a- to the carboxyl
group and their pharmacological activity resides mainly in the enantiomers of the
S-absolute configuration, the R-enantiomers being only weakly active or inactive
in in vitro test systems.

16. Many studies on chiral inversion are involved in 2-arypropionic acid (‘profens’)
NSAIDs, such as ibuprofen and ketoprofen.
ibuprofen and fenoprofen have been shown to undergo substantial unidirectional
chiral inversion from inactive (R)- to active (S)-enantiomer in humans and
animals .For most of NSAIDs, the Presence and degree of unidirectional (R) to
(S) chiral inversion is observed to be species dependent .The formation of CoA
thioesters of profens may make the (R)-enantiomer have significant toxicologic
implications due to potential Lipid incorporation.

17. Using a rat liver homogenate preparation, they reported
that the formation of ibuprofen CoA thioester was dependent
on both coenzyme A and ATP. Although synthetic samples of both (-)-(R)- and
(+)-(S)-ibuprofen CoA thioesters were found to undergo racemization and
hydrolysis on incubation with rat liver homogenates, only (-)-(R)-ibuprofen was
converted into a thioester enzymatically.

18.  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

19. Enantioselective metabolism by CYPs
 Microsomal enzyme
 Subtype : 2C9, 2D6, 2C19,2C9,3A4
7-hydroxylation CYP2C9 (S>>R)
 Warfarin 6-hydroxylation CYP1A2 (R>>S)
8-hydroxylation CYP1A2(R>>S)
10-hydroxylation CYP3A4 (R>>S)

21. Enantioselective metabolism by other
enzymes
 Phase II metabolism: Glucuronidation, Sulfation
 Propranolol UGT1A9 (S>>R)
UGT1A10 (R>>S)

22. Stereoselective glucuronidation of formoterol by human
liver microsomes
 Formoterol: active (R; R)- and inactive (S; S)-enantiomers
The kinetics of formation of formoterol glucuronides during incubation
of racemate and of single formoterol enantiomers with human liver microsomes
(n=9) was characterized by chiral HPLC assay.

24. Enantioselective first-pass metabolism and
oral bioavailability
Stereoselectivity in pharmacokinetics is observed for albuterol with a faster
disappearance of active (R)-enantiomer from human plasma irrespective of the
route of administration .This is mainly due to the enantioselective metabolism of
albuterol in favor of (R)-enantiomer, and this isomer has a 10-fold higher intrinsic
clearance value than its antipode . Furthermore, the degree of stereoselectivity
was highly dependent on the route of administration, with the lowest
concentration of (R)-albuterol observed after oral administration. The observed
oral bioavailability values of (R)- and (S)-albuterol were 9.4 and 68.7%,
respectively, a significant stereoselectivity in oral bioavailability due to the
substantial enantioselective metabolism on (R)-albuterol.

25. 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 twofold higher Cmax and AUC values of (R)-verapamil was due to a more than
twofold difference in the presystemic metabolism of two enantiomers in favor of
(S)-verapamil.

26. Glucoronidation
include the glucuronides of 2-phenylpropionic acid and
oxazepam, the glutamine conjugate of 4-chlorophenoxypropionic acid and the
glutathione conjugates of bromoisovalerylurea and bromovaleric acid.

27. The anti-inflammatory drug carprofen shows enantioselective glucuronidation

28. The major biliary metabolites of both (+)- and (-)-menthol are their
glucuronides, there being a twofold difference in the rates of their formation by
rat liver slices and by rat hepatic microsomes . The plasma elimination halflife of
(-)-menthol is 2.4 h compared with 4.0 h for (+)-menthol, with the plasma AUC of
(-)- menthol being threefold less than for the (+)- isomer. These pharmacokinetic
differences arise from the enormous difference between the Isomers in terms of
the biliary excretion of their glucuronides: 69% of a dose of the more rapidly
cleared (-)-menthol is excreted in the bile in 24 h compared with only 32% for
(+)-menthol.

29. Enantiomer–enantiomer interactions
Propafenone: This drug is extensively metabolized to 5-hydroxypropafenone
by human CYP2D6. the metabolism of two enantiomers of propafenone was
inhibited by each other in a competitive manner, and (R)-propafenone was a
stronger inhibitor towards 5-hydroxylation than its antipode.
Consistent with the in vitro observation, clearance of the (R)-enantiomer was
observed to be similar after oral administration of individual enantiomers or
racemic propafenone to Caucasians. In contrast, clearance of (S)-propafenone
was significantly lower after administration of racemate when compared with
administration of the (S)-enantiomer alone .As a consequence, dose-corrected
steady- state plasma concentrations of (S)-propafenone were higher following
administration of the racemate.

30. Enantioselective inhibition of metabolism of chiral drugs
by coadministered drugs
(R)-warfarin is metabolized by CYP3A4 and -1A2 and its antipode is mediated by
CYP2C9.
total warfarin plasma concentrations were increased when cimetidine or
sulfinpyrazone were coadministered. Concomitant pharmacotherapy of this chiral
drug with cimetidine decreases clearance of the (R)-enantiomer, but has no
influence on clearance of active (S)-warfarin .In contrast, sulfinpyrazone
Decreases clearance of the active (S)-isomer and, therefore, increases the
warfarin effects.

31.  benzbromarone, can also be explained by the enantioselective inhibition of
CYP2C9. Benzbromarone was a potent competitive inhibitor for (S)-warfarin
7- hydroxylation mediated by CYP2C9, resulting in enantioselective inhibition to
metabolism of the (S)-isomer.
 the AUC of (R)-metoprolol increased by 84% following the coadministration of
cimetidine, whereas that of the pharmacologically active (S)-enantiomer
increased
by 40%.

32. Influence of enzyme induction on
stereoselectivity in drug metabolism
Phenobarbital pretreatment altered the stereoselectivity in drug disposition and
metabolism of ifosfamide.
hydroxylation and dechloroethylation of ifosfamide were substantially
accelerated due to the CYP enzyme induction The increase in 4-hydroxylation of
the (S)-enantiomer was 12-fold and that for (R)-ifosfamide was 5-fold, such that
the net enantioelectivity was reversed in favor of (S)-ifosfamide compared with
those in untreated rats.

33. CYP2C19 is the major enzyme for metabolism of hexobarbital,
and it is inducible by rifampcin in humans Following oral administration of a
hexobarbital racemate, the (R)-enantiomer is preferentially metabolized
compared with its antipode. After administration of rifampcin to young
volunteers, clearance of (R)-hexobarbital was increased by 74%, whereas the
clearance of its antipode increased by 6% only. Thus, the therapeutic efficacy
should be diminished to a larger extent due to the induction and decreased drug
concentrations, especially (R)-hexobarbital (the active isomer).