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Title: Cytochrome P450 enzymes - Drug Interactions


1
Cytochrome P450 (CYP) enzymes - Drug
Interactions
  • P. Naina Mohamed
  • Pharmacologist

2
Introduction
  • Cytochrome P450 (CYP) is a family of isozymes
    responsible for the oxidation of organic
    substances.
  • CYP enzymes have been identified in animals,
    plants, fungi, protists, bacteria, archaea, and
    even in viruses.
  • In man there are around 30 CYP enzymes which are
    responsible for drug metabolism and these belong
    to families 14.
  • But, 90 of drug oxidation can be attributed to
    six main enzymes CYP 1A2, 2C9, 2C19, 2D6, 2E1
    and 3A4.
  • The most significant CYP isoenzymes in terms of
    quantity are CYP3A4 and CYP2D6.
  • CYP3A4 is found not only in the liver but also in
    the gut wall, where it may serve as a primary
    defence mechanism.
  • The present system of nomenclature for the
    various CYP isozymes employs a three-tiered
    classification, an Arabic numeral (family), a
    capital letter (subfamily) and another Arabic
    numeral (gene), e.g. CYP1A2 (Here CYP inmplies
    Cytochrome P450, 1 indicates family, A
    indicates subfamily and 2 indicates the gene).
  • These enzymes are heme-containing membrane
    proteins.
  • CYP3A4 isozyme has resulted in several clinically
    significant drug-drug interactions.

3
Introduction (Contd)
  • In humans, Cytochrome P450 enzymes are present in
    most tissues of the body, and they are located
    either in the inner membrane of mitochondria or
    in the endoplasmic reticulum of cells.
  • They play important roles in hormone synthesis
    and breakdown, cholesterol synthesis, and vitamin
    D metabolism.
  • They also function to metabolize potentially
    toxic compounds, including drugs and products of
    endogenous metabolism such as bilirubin,
    principally in the liver.
  • CYPs are the major enzymes involved in drug
    metabolism, accounting for about 75 of the total
    metabolism.
  • Most drugs undergo deactivation by CYPs, either
    directly or by facilitated excretion from the
    body.
  • Also, many substances are bioactivated by CYPs to
    form their active compounds.
  • Although a majority of the isozymes are located
    in the liver, extrahepatic metabolism also occurs
    in the kidneys, skin, gastrointestinal tract, and
    lungs.
  • Significant inactivation of some orally
    administered drugs is due to the extensive
    first-pass metabolism in the gastrointestinal
    tract by the CYP3A4 isozyme.

4
Introduction (Contd)
  • CYP2C19 and CYP2D6 are affected by genetic
    control.
  • Individuals lacking the gene for these isozymes
    are poor metabolizers.
  • Individuals possessing it are capable of normal
    drug metabolism and are considered extensive
    metabolizers.
  • Hepatic disease which affects organ function, and
    congestive heart failure which decreases blood
    flow to the liver affect the metabolism.
  • The cytochrome P450 monooxygenase system is more
    affected by aging than any other metabolic
    pathway .
  • Decreased biotransformation occurs in newborns
    due to underdevelopment of hepatic microsomal
    components.
  • In the elderly, decreases in hepatic blood flow,
    enzyme activity, and liver mass result in reduced
    metabolic activity.

5
CYP1A subfamily
  • The CYP1A family consists of two enzymes, 1A1 and
    1A2.
  • CYP1A1 is found mainly in the lungs, mammary
    glands, placenta and lymphocytes.
  • It is an enzyme involved in the inactivation of
    procarcinogens and is highly induced by
    polycyclic aromatic hydrocarbons (PAHs), which
    are found in cigarette smoke.
  • There is a strong association between the
    activity of CYP1A1 and the risk of lung cancer.
  • CYP1A2 is expressed mainly in the liver.
  • It is induced by cigarette smoking.
  • It is also induced by the ingestion of some
    foodstuffs such as cruciferous vegetables as well
    as barbecued or charbroiled food.
  • Some drugs such as omeprazole may induce CYP1A2
    activity.
  • Drugs such as theophylline, caffeine, imipramine,
    paracetamol and phenacitin are metabolized by
    CYP1A2.
  • Alteration in CYP1A2 activity, for example by
    smoking, may alter the requirements for
    theophylline among asthmatics and haloperidol
    among psychiatric patients.
  • Smokers have increased tolerance to caffeine due
    to smoking induced caffeine metabolism.

6
CYP2 family
  • The CYP2 family consists of CYP2A6, CYP2C9,
    CYP2C19, CYP2D and CYP2E1.
  • CYP2A6
  • It was previously known as coumarin hydroxylase.
  • It is a relatively unimportant enzyme in terms of
    the number of substrates which it metabolizes,
    one of the substrates broken down by this enzyme
    is nicotine.
  • CYP2C9
  • S-isoform of Warfarin is metabolized by CYP2C9.
  • There are a number of polymorphisms of the gene
    that encode this enzyme resulting in poor
    metabolic status.
  • Other drugs metabolized by CYP2C9 include
    non-steroidal anti-inflammatory drugs (NSAIDs)
    (including COX-2 selective inhibitors), the
    hypoglycemic agent tolbutamide, phenytoin and the
    angiotensin-II receptor antagonist losartan.
  • CYP2C19
  • Diaazepam (Benzodiazepam), Omeprazolle (Proton
    pump inhibitor), Propanolol (Beta adrenergic
    blocker) and the Amitriptyline (Antidepressant)
    are the main substrates of CYP2C19.

7
CYP2 family (Contd)
  • CYP2D6
  • Anti-arrhythmics such as flecanide and encainide,
    tricyclic antidepressants, some beta-blockers and
    a number of selective serotonin re-uptake
    inhibitors are metabloised (Substrates) by this
    enzyme.
  • Commonly used analgesics, including codeine and
    tramadol, are also broken down by this enzyme.
  • Previously it was named as debrisoquine
    hydroxylase,
  • CYP2E1
  • CYP2E1 was named previously as dimethylnitrosamine
    N-demethylase.
  • It is responsible for the metabolism of small
    organic compounds such as alcohol and carbon
    tetrachloride as well as the halogenated
    anaesthetic agents halothane, enflurane, diethyl
    ether, trichloroethylene, chloroform, isoflurane
    and methoxyflurane.
  • It is also responsible for the breakdown of many
    low molecular weight toxins and carcinogens, many
    of which are used in manufacturing and dry
    cleaning industry, including benzene, styrene,
    acetone, vinyl chloride and N-nitrosamines.
  • Some of these substances are pro carcinogens
    which are activated by CYP2E1.
  • There are gender differences in the expression of
    the enzyme, obesity and fasting may also affect
    its activity.
  • In China an association was detected between
    polymorphisms of CYP2E1 and oesophageal and
    gastric cancer.
  • There is also mounting evidence that CYP2E1 may
    be a key factor in the pathogenesis of alcoholic
    liver disease.

8
CYP3A subfamily
  • CYP3A4 is the most abundantly expressed drug
    metabolizing enzyme in man responsible for the
    breakdown of over 120 different medications.
  • It is an important area for study with respect to
    enzyme based drug interactions.
  • Among the drugs metabolized are sedatives such as
    midazolam, triazolam and diazepam, the
    antidepressives amitriptyline and imipramine, the
    anti-arryhthmics amiodarone, quinidine,
    propafenone and disopyramide, the antihistamines
    terfenadine, astemizole and loratidine, calcium
    channel antagonists such as diltiazem and
    nifedipine and various antimicrobials and
    protease inhibitors.

9
Mechanism of action of CYP enzymes
  • Substrate binds to the active site of the enzyme
  • Stimulation of conformational changes of the
    active site
  • Transfer of an electron from NAD(P)H
  • Reduction of the iron(III) (Heme center) of CYP
    enzyme to the ferrous state
  • Molecular oxygen binds covalently to the heme
    iron
  • Formation of dioxygen intermediate of P450
    enzymes
  • Reduction of the dioxygen adduct to a negatively
    charged peroxo group
  • Formation of a highly reactive species (P450
    Compound 1)
  • Catalyse a wide variety of reactions

10
Drug interaction
  • Changes in cytochrome P450 system determine the
    occurrence of several drug interactions that can
    result in drug toxicities, reduced
    pharmacological effect, and adverse drug
    reactions.
  • Many drugs may increase or decrease the activity
    of various CYP isozymes either by inducing the
    biosynthesis of an isozyme (enzyme induction) or
    by directly inhibiting the activity of the CYP
    (enzyme inhibition).
  • By recognizing whether the drugs involved act as
    enzyme substrates, inducers, or inhibitors, it is
    possible to prevent clinically significant
    interactions from occurring.
  • Avoiding coadministration or anticipating
    potential problems and adjusting a patient's drug
    regimen early in the course of therapy can
    provide optimal response with minimal adverse
    effects.

11
Enzyme induction
  • The effect of induction is simply to increase the
    amount of P450 present and speed up the oxidation
    and clearance of a drug.
  • Smoking and long-term alcohol or drug consumption
    and can reduce the duration of action of a drug
    by increasing its metabolic elimination.
  • The CYP1A2 enzyme can be induced by exposure to
    polycyclic aromatic hydrocarbons found in
    char-grilled foods and cigarette smoke. Since its
    activity is enhanced by smoking and eating
    grilled meat or cruciferous vegetables, it is
    difficult to obtain therapeutic effects of drugs
    like theophylline and propranolol.
  • Most human CYP2C and 3A subfamily proteins are
    induced by barbiturates.
  • Human CYP2E1 is inducible by ethanol and
    isoniazid.
  • Most drugs can exhibit decreased efficacy due to
    rapid metabolism, but drugs with active
    metabolites can display increased drug effect
    and/or toxicity due to enzyme induction.
  • The interactions due to enzyme induction take 2
    to 3 weeks to develop completely and are slow to
    resolve after stopping the enzyme inducer.

12
Enzyme inducers
  • The main drugs responsible for induction of the
    most clinically important cytochrome P450
    isoenzymes are
  • Griseofulvin
  • Phenytoin
  • Rifampicin
  • St. Johns wort
  • Carbamazepine
  • Phenobarbitone
  • Cigerette Smoke
  • GPRS Cell Phone

13
Enzyme induction
  • Rifampin or Carbamazepine or Barbiturates or
    Phenytoin or St. John's wort
  • Induction of hepatic metabolism (CYP3A4)
  • Decreased concentration of warfarin, quinidine,
    cyclosporine, losartan, oral contraceptives and
    methadone levels
  • Reduced therapeutic efficacy

14
Enzyme inhibition
  • Enzyme inhibition occurs when 2 drugs sharing
    metabolism via the same isozyme compete for the
    same enzyme receptor site.
  • The more potent inhibitor will predominate,
    resulting in decreased metabolism of the
    competing drug.
  • For most drugs, this can lead to increased serum
    levels of the unmetabolized entity, leading to a
    greater potential for toxicity.
  • For drugs whose pharmacological activity requires
    biotransformation from a pro-drug form,
    inhibition can lead to decreased efficacy.
  • Enzyme inhibition is more common than enzyme
    induction.
  • Enzyme inhibition can occur within 2 to 3 days,
    resulting in the rapid development of toxicity.

15
Enzyme inhibition
  • There are three basic types of enzyme inhibition
  • 1. Competitive inhibition
  • 2. Non-competitive inhibition
  • 3. Uncompetitive inhibition
  • competitive inhibition
  • Competition occurs between inhibitor and
    substrate for the same binding site on an enzyme.
  • For example, when single oral doses of metoprolol
    (50 mg), a beta-adrenoceptor blocking agent
    and/or propafenone (150 mg) were administered, an
    approximately two-fold reduction in the oral
    clearance of metoprolol was observed when
    propafenone was included. The dose of metoprolol
    should be reduced when propafenone is also given.
  • Similar drug-drug interactions are seen in the
    combined administration of thioridazine and
    propranolol (CYP2D6), fluoxetine and desipramine
    (CYP2D6), omeprazole and diazepam (CYP2C19),
    tolbutamide and phenytoin (CYP2C9), and diltiazem
    and cyclosporin (CYP3A).

16
Enzyme inhibition
  • Erythromycin or Ketoconazole
  • Inhibition of CYP3A
  • Blockade of Terfenadine metabolism
  • Increased plasma concentrations of Terfenadine
  • Prolongation of QT intervals
  • Cardiac dysrhythmia (Torsades de pointes)
  • In consequence, it has been reported that the
    metabolism of drugs like carbamazepine, midazolam
    and cyclosporin are catalysed by CYP3A, and their
    plasma concentrations are increased when its
    metabolism is inhibited by combined use with
    erythromycin.

17
Enzyme inhibition
  • Non-competitive inhibition
  • The inhibitor binds at a site on the enzyme
    distinct from the substrate, to produce the
    inhibition of enzyme.
  • Example Interactions between cimetidine and a
    number of drugs.
  • Cimetidine
  • Bound to haem portion of P450
  • Formation of a stable cytochrome-substrate
    complex
  • Inhibition of phase I drug metabolism reactions
    (i.e. hydroxylation, dealkylation)
  • Prevention of access of other drugs to the P450
    system
  • Cimetidine does not inhibit conjugation
    mechanisms including glucuronidation, sulphation
    and acetylation, or deacetylation or ethanol
    dehydrogenation.

18
Enzyme inhibitors
  • The main drugs responsible for inhibition of the
    most clinically important cytochrome P450
    isoenzymes are
  • Sulphonamides
  • Antifungals ( Itraconazole, Ketoconazole,
    Fluconazole)
  • Macrolide Antibiotics (Clarithromycin,
    Azithromycin, Erythromycin)
  • Ciprofloxacin
  • Sertraline
  • Cimetidine
  • Omeprazole
  • Metronidazole
  • Antivirals (Ritonavir, Indinavir, Nelfinavir,
    Amprenavir)
  • Antiarrhythmics (Amiodarone, Quinidine)
  • Antidepressants (Fluoxetine, Paroxetine)
  • Isoniazid
  • Alcohol
  • SICK FACES.COM

19
Clinical examples of P450-based interactions
  • Terfenadine and Macrolides (Erythromycin) or
    Azole antifungals (Ketoconazole)
  • Cimetidine and Disopyramide
  • Grape Fruit Juice and Felodipine
  • Grape Fruit Juice and benzodiazepines (e.g.
    midazolam, triazolam) or antihistamines (e.g.
    terfenadine) or immuno-suppressive drugs (e.g.
    cyclosporin).
  • Omeprazole and Phenytoin or Diazepam

20
Enzyme inhibition
  • Ketoconazole, Erythromycin, or Grapefruit juice
  • Inhibition of CYP3A4
  • Blocks metabolism of Terfenadine
  • Increased plasma levels of Terfenadine
  • Fatal cardiac arrhythmias (torsades de pointes)
  • Withdrawn from the market

21
Enzyme inhibition
  • Gemfibrozil (and other fibrates)
  • CYP3A inhibition
  • Prevents metabolism of Statins (HMG-CoA reductase
    inhibitors)
  • Increased plasma levels of Statins
  • Rhabdomyolysis

22
Enzyme inhibition
  • Ritonavir, indinavir, nelfinavir, amprenavir or
    saquinavir
  • Inhibit CYP3A4
  • Blocks metabolism of Phosphodiesterase type-5
    inhibitors (Sildenafil, Tadalafil, Vardenafil)
  • Increased serum levels PDE5 inhibitors
  • Excessive vasodilation
  • Hypotension

23
Enzyme inhibition
  • Cimetidine
  • Inhibitor of multiple CYPs
  • Increased concentration of warfarin, theophylline
    and phenytoin
  • Toxicity

24
Enzyme inhibition
  • Amiodarone
  • Inhibitor of many CYPs and of P-glycoprotein
  • Decreased clearance (risk of toxicity) for
    warfarin, digoxin and quinidine
  • Increased Plasma levels
  • Toxicity

25
Inhibition or induction of first-pass metabolism
  • The gut wall contains metabolising enzymes,
    principally cytochrome P450 isoenzymes.
  • Some drugs can have a marked effect on the extent
    of first-pass metabolism by inhibiting or
    inducing the cytochrome P450 isoenzymes in the
    gut wall or in the liver.
  • Grapefruit juice
  • Inhibits the cytochrome P450 isoenzyme CYP3A4
  • (mainly in the gut)
  • Reduction of the metabolism of oral
    calcium-channel blockers
  • Increased Plasma levels of CCBs

26
Genetic factors in drug metabolism
  • Some of the population have a variant of the
    isoenzyme with different (usually poor) activity.
  • For example, a small proportion of the population
    have low CYP2D6 activity and are described as
    poor or slow metabolisers (about 5 to 10 in
    white Caucasians, 0 to 2 in Asians and black
    people). The majority who possess the isoenzyme
    are called fast or extensive metabolisers.
  • CYP2D6, CYP2C9 and CYP2C19 also show
    polymorphism, whereas CYP3A4 does not.

27
Cytochrome P450 isoenzymes and predicting drug
interactions
  • Prediction of drug interactions may reduce the
    numbers of expensive clinical studies in subjects
    and patients and avoids waiting until
    significant drug interactions are observed in
    clinical use.
  • If a new drug is shown to be an inducer, or an
    inhibitor, and/or a substrate of a given
    isoenzyme, we can predict likely drug
    interactions by using the list of enzyme
    inducer/inhibitor/substrate.
  • For example, ciclosporin is metabolised by
    CYP3A4, and rifampicin (rifampin) is a known,
    potent inducer of this isoenzyme, whereas
    ketoconazole inhibits its activity. Hence,
    rifampicin reduces the levels of ciclosporin and
    ketoconazole increases them.

28
Conclusion
  • Understanding the mechanism underlying drug
    interactions is useful, not only in preventing
    drug toxicity or adverse effects, but also in
    devising safer therapies for disease.

29
References
  • Stockleys Drug Interactions, 9th Edition
  • Karen Baxter
  • Goodman Gilman's The Pharmacological Basis of
    Therapeutics, 12e Laurence L. Brunton, Bruce A.
    Chabner, Björn C. Knollmann
  • Basic Clinical Pharmacology, 12e Bertram G.
    Katzung, Susan B. Masters, Anthony J. Trevor
  • Tintinalli's Emergency Medicine A Comprehensive
    Study Guide, 7e Judith E. Tintinalli, J. Stephan
    Stapczynski, David M. Cline, O. John Ma, Rita K.
    Cydulka, and Garth D. Meckler The American
    College of Emergency Physicians
  • Harrison's Online Featuring the complete contents
    of Harrison's Principles of Internal Medicine,
    18e Dan L. Longo, Anthony S. Fauci, Dennis L.
    Kasper, Stephen L. Hauser, J. Larry Jameson,
    Joseph Loscalzo, Eds
  • CURRENT Diagnosis Treatment in Family Medicine,
    3e Jeannette E. South-Paul, Samuel C. Matheny,
    Evelyn L. Lewis

30
References
  • http//www.ncbi.nlm.nih.gov/pmc/articles/PMC131224
    7/
  • http//www.aafp.org/afp/2007/0801/p391.html
  • http//www.edhayes.com/CYP450-2.html
  • http//www.nutritionandmetabolism.com/content/5/1/
    27
  • http//www.ncbi.nlm.nih.gov/pubmed/16248836
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