Transcript Snímek 1

Charles University in Prague, Third Faculty of Medicine
Cycle II, Subject: General pharmacology
Lecture: 14th November 2012 8:00-9:30, Burian Hall, Ruská
87, Prague
Drug metabolism
Prof. M. Kršiak
Department of Pharmacology, Third Faculty of Medicine, Charles University
in Prague
METABOLIC (biotransformation)
mostly in the liver
the drug is made more polar, hydrophilic – this increases its
excretion in the urine
PHASE 1 > PHASE 2 …
ENZYME INDUCTION/ INHIBITION
CYPs - cytochrom P450, microsomal enzymes, oxidases GENE POLYMORPHISM
EXCRETION
mostly by the kidneys
metabolites or unchanged
GIT... enterohepatic circulation e.g. tetracyclines
Lungs (volatile anaesthetics)
PHASE 1 REACTIONS
OXIDATIONS
are the most common reactions and these are
catalysed by an important class of enzymes called
microsomal enzymes or
CYTOCHROME P-450 (CYP-P450)
Other, relatively uncommon, Phase I reactions are
reductions and hydrolysis
Phase 1 reactions often introduce a reactive group, such as
hydroxyl, into the molecule, this group then serves as the point
for the conjugating system to attach a substituent such as
glucuronide
Downloaded from: StudentConsult (on 11 November 2012 11:34 AM)
© 2005 Elsevier
PHASE 2 REACTIONS
Phase 2 reactions involve CONJUGATION (i.e.
attachment of a substituent group),
which usually results in inactive metabolites,
occasionally in active metabolites (e.g. morphine6-glucuronide is an active metabolite of
morphine)
The groups most often attached are
glucuronyl, sulfate, methyl and acetyl
CYTOCHROM P-450 (CYP-450s or CYPs)
Cytochrome P450 monooxygenase system,
microsomal enzymes, microsomal oxydases
1/ CYPs are the major enzymes involved in drug metabolism,
accounting for about 75% of the total metabolism.
2/ The cytochrome P450 is a large group of enzymes that catalyze
the oxidation of organic substances.
3/ They contain a heme cofactor and, therefore, are hemoproteins
4/ Activity of CYPs can be inhibited or increased by drugs (or other
chemicals) - ENZYME INHIBITION/INDUCTION that may be of great
importance in therapeutics.
5/ There are many isoforms of CYPs, some with important individual
differences in gene expression due to GENE POLYMORPHISM that
may be of great importance in therapeutics.
ENZYME INHIBITION
(Inhibition of CYP-450, microsomal enzymes
rapidly occuring (after the 1st dose)
may cause adverse drug interactions (increased toxicity
of drugs that are deactivated by the enzyme)
e.g. clarithromycin (a macrolide antibiotic) may increases effects of
warfarin (an anticoagulant)
grapefruit juice may increase effects of calcium channel blockers
(antihypertensives, antidysrhytmic drugs)
ENZYME INDUCTION
(Induction of CYP-450, microsomal enzymes
Repeated administration of some drugs increases (in
2-3 days) the synthesis of CYP-450 = enzyme
induction
may cause adverse drug interactions:
mostly decreased effects of drugs that are deactivated by
the enzyme
e.g. rifampicin (anti-tuberculosis drug) reduces effects of
sex hormones (oral contraceptives) or of warfarin
(anticoagulant)
There are many isoforms of CYPs
Genetic polymorphisme exists for CYP2C9 expression because
the CYP2C9 gene is highly polymorphic. Some 100 therapeutic
drugs are metabolized by CYP2C9, including drugs with a
narrow therapeutic index such as warfarin
CYP2C19
CYP2C9
CYP3A4
CYP3A4 is involved in the
metabolism of about 50% of
drugs. Gene polymorphism
CYP 3A4 does not practically
influence interindividual
variability
CYP2D6
CYP2D6 shows the largest phenotypical variability among the
CYPs, largely due to genetic polymorphism
active metabolites:
O-demethylation
[CYP2D6]
codeine -> morphine
oxycodone -> oxymorphone
N-demethylation
hydrocodone-> hydromorphone
[CYP3A4] nor-derivates
Glucuronidation*
*[UGT]
morphine -> morphine6-glucuronide [M6G]
*[UGT] uridine diphosphate
glucuronosyl transferase
morphine
codeine
dihydrocodeine
hydrocodone
oxycodone*
hydromorphone
3
-OH
-OCH3
-OCH3
-OCH3
-OCH3
-OH
6
-OH
-OH
-OH
=O
=O
=O
7-8
//
//
/
/
/
/
*–OH at C14
tramadol hydrochloride
(±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride
O-demetylation
[CYP2D6]
[tramadol – >demethyl tramadol (M1 metabolite)]
CYP 2D6 GENE POLYMORPHISM
No. of subjects
Rapid +intermediate
metabolizers
Poor
metabolizers
7-10 %
Ultrarapid
metabolizers
2-3(7)%
Rate
Ultrarapid metabolizers have extra copies of genes for CYP 2D6. They make more enzyme than normal.
Ultrarapid
Metabolizers
Ultrarapid metabolizers may break down some drugs (e.g. some antidepressants) so quickly that the drug
does not need to help at usual doses.
They may also need a lower dose of a drug, in the case where a drug is metabolized in active metabolites
(e.g. in some opioid analgesics)
Poor metabolizers have variants of genes for CYP 2D6 that do not work normally. They make much less
enzyme than normal or none at all.
Poor
Metabolizers
Poor metabolizers have a higher risk for side effects from some drugs (e.g. some antidepressants) and
may need to avoid those drugs or take a lower dose.
They may also need a higher dose of a drug, in the case where a drug is metabolized in active metabolites
(e.g. in some opioid analgesics)