‫‪CYP 450 and Drug‬‬

‫‪Interaction‬‬
‫פרופ' גריס יעקוב‬
‫מחלקה פנימית א'‬
‫מרכז רפואי רמב"ם‬
:Xenobiotic Metabolizing Enzymes
 Phase I: (Oxygenase)- Functionalization
 Cytochrome P450s (CYP 450)
 Falvin-containing monooxygenase (FMO)
 Epoxide Hydroxylase (EH)
 Phase II: (Transferase, [conjugation])
 Sulfotransferase (SULF)
 Glucoronosyltransferase (UGT)
 Glutathion-S-transeferase (GST)
 Other Enzymes
 Alcohol Dehydrogenases
 Aldehyde Dehydrogenases
Cytochrome P-450 enzyme system
H+ + NADPH + R + O2

CYP450 )Phase – I)

NADP+ + H2O + RO
The most important system for drug
biotransformation & metabolism
:Location of CYP450

 Lipophilic membrane of the ER

 Microsomes vescicles (non-ribosomal ER)

 Liver, Gut, Kidney and less in other tissues

The Enzyme CYP450 : is

 Mixed Function Oxidase (MFO)

 HEME- containing enzymes

 Metabolizing single or multiple drug

:CYP 450Classification
 12 genes families (60% amino acids) are
known in humans (CYP italic)
 The major families are 1,2,3: CYP1,2,3
 Sub-families according to the amino acids
sequence similarities A, B, C..: CYP1A,
CYP2D etc.
 Individual enzymes (arabic numerals) 1,2..
CYP3A4, CYP 2D6 etc = 50 are known
CYP450 Nomenclature
Family

CYP2D6
Sub-Family Individual Gene
:Enzyme Isoforms
 CYP1 gene family: 1A1 and 1A2
 CYP1A2 is induced by smoking x3
 CYP2 gene family: is the largest family (5)
 CYP2D6 (liver and gut)
 CYP2C9
 CYP2E1 (induced by ethanol)
 CYP2E9 (warfarin and phentoin)
 CYP3 gene family
 CYP3A4 is the major enzyme (liver and gut)
CYP450:
 One Liver cell can contain a variety of
CYPs
 The most common individual enzymes:
 CYP3A4 ~50% liver & gut
 CYP2D6
 CYP2C9
 CYP2E1
 CYP2A6
 Drug Metabolizing Enzymes
 Liver is the major organ for drug metabolism / elimination
 Phase I and Phase II Enzymes
 Phase I: oxidative or hydrolytic reactions

 Phase II: conjugative reactions (‫(הידרופיליזציה‬

 Predominate enzyme system that metabolizes drugs is the

cytochrome P450 (CYP450) family of enzymes which
mediate oxidation reactions, such as hydroxylations
Proportions of CYP450 Enzymes
CYP450 Known Drugs Metabolized
In Human Liver
CYP1A2 4%

CYP2C9 10%
Other CYPs 3A4
CYP2C19 2%
2C9/19
2A6 CYP2D6 30%
2E1 2D6
1A2
CYP3A4 50%
Many CYP450 Enzymes Are
Polymorphic: Example CYP 2D6

• Responsible for
metabolism of
40% of all Rx
drugs
• Over 300
million Rx’s for
drugs with
polymorphism
per year
Family: CYP 2
Subfamily: CYP 2D6
Gene: CYP 2D6*3
Enzyme characteristics
% of drugs metabolised by enzyme

 3A4 50%
 2D6 25%
 1A2 15%
 2C9 Small no., but significant interactions

 2C19 Small no., but significant interactions

 2E1 ? toxicity
:Genetic Polymorphism
 Inherited autosomal recessive trait
 Genetic differences explain the inter-
individual variations in drug
biotransformation: Phenotypes
 PM: Poor Metabolizer (increased side effects)
 IM: Intermediate Metabolizer
 EM: Extensive Metabolizer
 UM: Ultrarapid Metabolizer
Genetic Polymorphism: e.g.
 CYP2D6 metabolizes propafenone
timolol
metoprolol
imipramine
perphenazine

Codein is metabolized (hydroxylation) to morphine

 CYP2D6 is absent in ~ 8% of caucasian
(PM-poor metabolizer)
Frequency of CYP2D6 Phenotypes in White Populations
Enzyme Characteristics
Interindividual Variability in Enzyme Content

 CYP3A4 x5
 CYP2D6 > 50
 CYP1A2 x 20
 CYP2C9 x5
 CYP2C19 ?
 CYP2E1 x 12
 Metabolic Drug Interactions

 Inhibition Activity Drug Conc.

 Induction
Activity Drug Conc.

 Polymorphism (CYP2D6)

 Formation of reactive, toxic, or active metabolites

 Disease state
Induction and Inhibition of CYP:

 Affects significantly the phenotype:

 IM induction EM
 IM inhibition PM

 Alters t1/2 and bioavailability of the drugs

:Inhibition and Induction
 Genotype
 Age dependent:
Birth: 2-4 wk
Elderly: the liver mass and flow are
decreased
 Disease dependent: e.g., alcoholism,
hepatitis, cirrhosis, intestine diseases
 Concomitant drugs
:CYP Inhibition
 The most CYP system become PM
 Prolonged pharmacologic effects
 Increased incidence of drug side effects
and toxicity
Grapefruit (naringin) inhibit CYP3A4 activity in gut
mucosa >> Bioavailability of many drugs
increase:
cyclosporine, felodipine and terfenadine
CYP Inhibition:continue
Erythromycine, clarithromycine, ketoconazole and
itraconazole are potent inhibitors of CYP3A4

Lovastatine cause severe myopathy when

administered with the above drugs

Terfenadine and astemizole cause severe

arrhythmia (QT prolongatioin and TdeP)
:CYP induction
 The effect occurs after 2-7 days
 Auto-induction can occur

Rifampin is a potent inducer of CYP3A4 and

in many cases the dose of a co-
administered drugs must be increased:
Cyclosporine, warfarin, verapamil,
metronidazole, methadone etc.
CYP Induction:continue
 CYP1A2 is induced by cigarette smoking:
we must increase the dose of aminophyllin

 CYP2E1 is induced by ethanol:

affects the metabolism of acetaminophen

 Phentoin and phenobarbital can induce all

cytochrome P (CYP-450) enzymes
:CYP2C9

Substrates Inducers Inhibitors

S-warfarin Rifampin Ketoconazole

Phentoin Barbiturates Metronidazole

NSAIDs Fluconazole

Tolbutamide Itraconazole
:Warfarin
 Is a racemic mixture R-warfarin and S-
warfarin (the most active)
 CYP2C9 is the main metabolizer of S-form
 CYP2C9 is inhibited by Fluconazole
Metronidazole
Amiodarone
 Atrial fibrillation: warfarin and amiodarone
:Warfarin
 CYP2C9*1 is the wild type
 CYP2C9*2 and *3 are variants and known to
decrease metabolism of warfarin and are
associated with risk for bleeding
 Homo- and heterozygotes dependent
 The quantity of CYP in liver decrease with age
(age dependent)
 Thus age and genotype are determinants of the
dose
:CYP3A4
Substrates Inducers Inhibitors
Amiodarone Carbamazipine Amiodarone
Cisapride Cortisone Cimitidine
Enalapril Rifampine Macrolides
Cyclosporine Spirinolactone Ca-antagonists
Ca-antagonists Phentoin Indinavir
Warfarin Ketoconazole
Lidocaine Fluconazole
Ketoconazole Grapefruit juice
Midazolam
Theophyllin
:CYP2D6

Substrates Inducers Inhibitors

Beta-blockers No identified drugs Fluoxetine
Omeprazole Sertraline
Codein Desipramine
Flecainide Cimitidine
Tricylic- Halopiridol
antidepressant
Mexilitine
Codeine intoxication
 Codeine (10%) is converted to morphine by
CYP2D6 (EMs)
 Codeine is metabolized (inactivated) by
CYP3A4 in the liver
 PMs 7% of the population are not affected
by this drug
 UMs 1-7% of the population require low
doses (Ethiopian are 25% Ums)
Metabolic Pathways of Codeine Biotransformation

Subject with CYP2D6 UM

and CYP3A4 PM could

increase the concentration of

morphine by 10 times

Morphine intoxication
Pharmacogenetics of Nortriptyline
Dose Adjustment according to CYP2D6 phenotype

Drug PM IM EM UM
Olanzapine 50 100 120 160
Thioridazine 35 80 125 165
Haloperidol 65 90 110 125
Venlafaxine 65 85 105 130
Maprotiline 35 75 120 170
(CYP2C19: (absent in 20% S. Asian

Substrates Inducers Inhibitors

Diazepam Rifampine Steroids

Propranolol Fluoxitine

Omeprazole Omeprazole

Phentoin Ritonavir

Imipramine
CYP2C19:
 3% of Caucasian are PMs
 15-20% of southern Asian are PMs
Ulcer cure
 In PMs omeprazole is effective about 100%
 In UM omeparazole is effective about 20%
:CYP2E1

Substrates Inducers Inhibitors

Acetaminophen Ethanol Disufiram

Ethanol Isoniazid

Halothane

Methoxyflurane
CYP2E1:
 Ethanol is an Inducer of CYP2E1
 Acetaminophen (Acamol) is metabolized
true this enzyme
 Reactive metabolite are increased with
alcohol drinking
 Acamol hepatotoxicity increased
significantly with alcohol drinking.
:CYP1A2

Substrates Inducers Inhibitors

Acetaminophen Cigarettes Cimitidine

Theophyllin Omeprazole Ciprofloxacin

Caffeine Rifampin Erythromicin

R-warfarin phenobarbital Grapefruit juice