CYTOCHROME P450

\\CYTOCHROME P450 enzymes

/metabolise drugs
/more than 50 enzymes
\6 metabolize 90 percent of drugs
/CYP3A4 and CYPD2D6 are the
most significant
\\GENETIC VARIABILITY / Polymorphism
/polymorphisms in enxymes may change response to
prescribed drug CLASSES
\BETA BLOCKERS
\ANTI DEPRESSANTS
/Cytohchrome P450
\may be inhibited or induced by drug / this
causes drug-drug interactions (unanticipated adverse
reactions r therapeutic failures)
WARFARIN
ANTIDEPRESSANTS
ANTIEPILEPTIC
STATINS

>>>
CYTOCHROME P450 ENZYME

******EVERYONE IS SUBJECTED DIFFERENT ENZYME

POLYMORPHISM****
******EVERYONE IS SUBJECTED DIFFERENT ENZYME
POLYMORPHISM****
******EVERYONE IS SUBJECTED DIFFERENT ENZYME
POLYMORPHISM****

\\Cytochrome P450 (CYP450)

/enzyme for making:
\CHOLESTEROL
\STEROIDS
\PROSTACYCLINS
\THROMBOXANE A2
/also detoxify foreign chemicals and metabolisms of
drugs
/they are bound to membranes inside cell (CYT)
/contain heme pigment (CHROME and P)
\absorbs light @ wavelength of 450 nm

when exposed to carbon monoxide (WHAT DOES THIS

MEAN?)
/CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5
\metabolize 90% of drugs
\predominantly expressed in liver
\small intestines as well
/REDUCES BIOAVAILABILITY
\lungs, placenta, kidneys as well

\\PHARMOCOGENETICS
/1 out of every 15 WHITE or BLACK persons may have
exaggerated

response

to

standard

doses

of

BETA

BLOCKERS
\metoprolol [LOPRESSOR]
\or no response to the analgesi tramadol
(ULTRAM)
\CYP450 MESSED UP METABOLISM due to
polymorphism
/A specific gene encodes each CYP450 enzyme
\every person inherits one genetic allele from
each parent
/"WILD TYPE" or "VARIANT" (wild

type most common)

/"EXTENSIVE"

metabolizer

has

received two copies of wild-type allels

/POLYMORPHISM OCCURS WHEN VARIANT ALLELE
REPLACES ONE OR BOTH WILD-TYPE ALLELS
\VARIANT ALLELES usually encode a CYP450
that has reduced or no activity
\Persons with two copies of variant alleles =
"POOR" Metabolizers
/those with one wild-type and one
variant allele have reduced enzyme activity
/Some persons inherit multiple copies of wild-type
alleles
\EXCESS ENZYME ACTIVITY
/"ULTRARAPID" METABOLIZER
\\CYP450 POLYMORPHISM
/Responsible for observed variation in drug response in
patients of dif ethnic origins
\7% White ppl, 2-7% black ppl are POOR
Metabolizers of drugs dependent on CYP2D6
/CYP2D6 metabolizes many BETA
blockers, antidepressants and opioids

\1 in 5 Asian persons is a poor metabolizer of

drugs dependent CYP2C19
/Metabolizes

PHENYTOIN

(Dilantin), PHENOBARBITAL, OMEPRAZOLE (Prilosec),

and other ###FIND OUT MORE###

\\CLINICAL RECOMMENDATION
/"Genotype testing may predict persons who are poor
metabolizers or are nonresponsive to drugs metabolized by
CYP450 enzymes"
\Large prospectibve trials needed
/"Genetic Variations in CYP450 metabolism should be
considered when patients exhibit unusual sensitivity or
resistance to drug effects at normal doses
\Studies demonstrate a link between
adverse effects and variant CYP450 alleles
/"Patients
development

should

be

of adverse

monitored
drug

effects

closely
or

for

the

therapeutic

failureswhen a potent CYP450 enzyme metabolized by one

or more CYP450

enzyme"

\Well-recognized
significant drug interaction

cause

of

clinically

/"Severe toxicity can result if CYP450 enzyme-inhibiting

drugs are added to the following medications: atypical,
antipsychotics, benzodiazepines, cyclosporine
(Sandimmune), slatins, or warfarin (Coumadin)
\particularly

true

if

substrate

drug

depends on only one CYP450 enzyme for metabolism

/"Because they are known to cause cliniclly significant
CYP450 drug interactions, always use caution when
adding the following substances to medications that
patients
(CORDARONE),

are

taking:

AMIODARONE

ANTIEPILEPTIC

DRUGS,

ANTIDEPRESSANTS,

ANTITUBERCULAR

DRUGS,

GRAPEFRUIT JUICE, MACROLIDE AND KETOLIDE

ANTIBIOTICS,

NONDIHYDROPINE,

CALCIUM

CHANNEL BLOCKERS, OR PROTEASE INHIBITERS"

\Are

either

potent

inhibiters

or

inducers of CYP450 enzymes

\\DRUG INTERACTIONS
/Many drug interaction result from alteration of
CYP450 metabolism
\terfenadine

(Seldane),

astemizole

(Hismanal), gastrointestinal motility agent cisapride

(Propulsid),
/withdrawn
because

metabolic

inhibition

from
by

US

other

Market

drugs

(life-

threatening arrhythmias)
/Calcium channel blocker mibefradil (Posicor) also
withdrawn '98 - potent enzyme inhibitor that resulted in
toxic levels of other cardiovascular drugs
/Drugs interact with CYP450 system in many ways+
\can

be

metabolized

by

only

one

(metoprolol by CYP2D6)
\multiple

enzymes

(e.g.,

warfarin

[Coumadin] by CYP1A2, CYP2D6, CYP3A4)

\drugs that cause CYP450 metabolic Dr.int.
are INHIBITORS or INDUCERS
/Inhibitors block metabolic activity
of 1+ CYP450 enzymes
/dose and ability to bind to
enzyme affects the extent of metabolism
/sertraline (Zoloft) is a mild
inhibitor of CYP2D6 at 50 mg (200 mg = potent) effects occur fast

SIGNIFICANT
THEIR

CYTOCHROME

P450

INHIBITORS,

ENZYMES

INDUCERS,

AND
AND

SUBSTRATES\\\\\\\\\\\
\ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \\ \ \ \ \ \ \ \ \
\\\
\ \ \ \CYP1A2
\ \Potent inhibitors
\Amiodarone (Cordarone)
\cimetidine (Tagamet)
\ciprofloxacin (Cipro)
\fluvoxamine (Luvox)
\ \potent inducers
\Carbamazepine (Tegretol)
\phenobarbital
\rifampin (Rifadin)
\tobacco
\ \substrates
\Caffeine
\clozapine (Clozaril)
\teheophylline
\ \ \ \CYP2C9
\ \potent inhibitors

\Amiodarone (Cordarone)
\fluconazole (Diflucan)
\metronidazole (Flagyl)
\fluvoxamine (Luvox)
\ritonavir (Norvir)
\trimethoprim/sulfamethoxazole
(Bactrim, Septra)
\ \potent inducers
\Carbamazepine (Tegretol)
\phenobarbital
\rifampin (Rifadin)
\tobacco
\ \substrates
\Caffeine
\clozapine (Clozaril)
\teheophylline
\ \ \ \CYP2C19
\ \potent inhibitors
\Fluvoxamine
\isoniazid (INH)
\ritonavir
\ \potent inducers
\Carbamazepine

\phenytoin
\rifampin
\ \substrates
\Omeprazole (Priolsec)
\phenobarbital, phenytoin
\ \ \ \CYP2D6
\ \potent inhibitors
\Amiodarone
\cimetidine
\diphenhydramine (Benadryl)
\fluxetine
\paroxetine (Paxil)
\quinidine
\ritonavir
\terbinafine

\ \potent inducers
\No Significant inducers
\ \substrates
\Amitriptyline
\carvedilol
\codeine
\donepezil (Aricept)
\haloperidol (Haldol)

\metaprolol (Lopressor)
\paroxetine
\risperidone (Risperdal)
\tramadol (Ultram)

\ \ \ \CYP3A4 and CYP3A5

\ \potent inhibitors
\Clarithromycin (Biaxin)
\diltiazem (Cardizem)
\erythromycin
\grapefruit juice
\itraconazole (Sapranox)
\ketoconazole (Nizoral)
\nefazodone (Serzone)
\ritonavir
\telithromycin (Ketek)
\verapamil (Calan)

\ \potent inducers
\Carbamaepine
\Hypercium
Jonh's wort)
\phenobarbital
\phenytoin
\rifampin

\ \substrates

perforatum

(St.

\Alprazolam (XANAX)
\amlodipine (NORVASC)
\atorvastatin (LIPITOR)
\cyclosporine (SANDIMMUNE)
\diazepam (VALIUM)
\estradiol (ESTRACE)
\simvasatin (ZOCOR)
\sildenafil (VIAGRA)
\verapamil zolpidem (AMBIEN)
\\Drug can be metabolized by and inhibit same enzyme
(e.g., erythromycin)
\can also be metabolized by one enzyme and
inhibit another enzyme (e.g., terbinafine [Lamisil])
\intentionally combined to take advantage of
CY450 Inhibition
\Ritonavir

(Norvir)

protease

inhibitor and potent CYP3a4 inhibitor + lopinavir (Kaletra)

to amp serum levels with human immunodeficiency virus
\Inducers increa CYP450 enzyme activity by increasing
enzyme synthesis
\there is delay before enzyme activity increases depending on half-life of drug induced
\decrease contentration of drug metabolized by
CYP2C9 can occur ~24hours~ after inducing of Rifadin -

inducer w/ short half-life

\can

go

up

to

one

week

after

taking

phenobarbital - inducer w/ long half-life

\metabolized by same CYP450 enzyme that
induces
\Carbamazepine

(Tegretol)

potent enzyme inducer - must start at low dose then

increased at weekly intervals - half life gradually decreases
over time

ADVERSE DRUG EFFECTS

\Standard doses may cause adverse effects related to
elevated drug serum levels if one has poor metabolizer or
CYP450 enzyme inhibitor added
\effects are more likely if drug has narry saftey
range or dependent on only 1 enzyme for metabolism
\A woman was treated with Paxil for panic disorder
\she developed hypertension
\prescribed 50 mg daily of extended-release
meoprolol (Toprol XL)
\woman becomes symptomatically orthostatic
###FIND OUT MORE###
\metoprolol is metabolized solely by CYP2D6, and
present in higher serum levels because of paroxetine

\Peak serum levels of Zocor (Metabolized solely by

CYP3A4)

can

increase

by

lot

w/

those

with

poor

metabolizers or w/ addition of potent inhbitor

\e.g., verapamil [Calan], nefazodone [Serzone;
brand not available in US]), increasing risk of myopathy +
rhabdomyolysis at usual doses
\Some drugs like dramadol or losartan (COZAAR) are not
therapeutic until they are metabolized by active compounds
\known as prodrugs - can cause exaggerated
therapeutic effect or adverse effect when CYP450 inducer is
added
\if CYP450

inhibitor is combined with a

prodrug, or a person has poor metabolizer of a prodrug,

therapeutic failure is likely because of no production of the
active drug
GENOTYPE TESTING
\Genotyping for CYP450 polymorphism has been for
reasearch purposes or drug trails
\FDA approved first genotype test for physicians to guide
selection of medications metabolized by CYP450 enzymes
\Amplichip CYP450 test is a DNA microarray that can detect
29

polymorphisms of CYP2D6 and two polymorphisms of

CYP2C19 using blood sample

\There is evidence ofa link between adverse effects and

polymorphisms coding for reduced CYP450 activity, large

prospective clinical trials are needed to determine whether use
of genotyping in clinical practice is cost-effective and improves
outcomes by preventing adverse drug effects or identifying poor
responders