Xenobiotics Flashcards by Denisse Tiangco

Compound that is foreign to the body

Compounds in plant food, and synthetic compound in medicines, food additives, and environmental pollutants

Xenobiotics

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Drugs
Chemical carcinogens
Various compounds

that have found their way into our environment like PCB’s and insecticides

Xenobiotics

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Xenobiotics are metabolized or excreted

unchanged

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Xenobiotics biologic effects:

Pharmacologic responses
Toxicity
Immunologic reactions
Cancer

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Phase 1 of Xenobiotic Metabolism

Main reaction involved

Hydroxylation

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Phase 1 is catalyzed by

CYP 450

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Deamination
Dehalogenation
Desulfuration
Epoxidation
Peroxygenation
Reduction

Phase 1

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To increase water solubility (polarity) and thus excretion from the body

Purpose of the 2nd phase of metabolism

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Persist in adipose tissue indefinitely

Very hydrophobic xenobiotics

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Conjugation with glucoronic acid
Sulfate
Acetate
Glutathione
Certain amino acids
Methylation
Catalyzes by enzymes such as glucuronosyltransferases, sulfotransfersases, glutathione s-transferases using UDP-glucoronic acid, PAPS (active sulfate) and glutathione respectively as donors

Phase 2

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Xenobiotics are metabolized mainly in the

liver

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Convert the parent drug to a more polar metabolite (active or inactive)

Phase 1 reaction

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Endogenous substrate combines with the newly incorporated functional group to form a highly polar conjugate

Phase II reactions

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A nonpolar drug absorbed goes into

Phase 1

Modified metabolite
Inactive metabolite

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Hydrophilic drugs goes straight to

Excretion or elimination

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A slightly polar drug goes to

Phase 2

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59/M, Stroke
Aspirin
Clopidogrel
Atorvastatin

Occasional epigastric pain when taking these drugs

Which is discouraged to be given to this patient?

a. Ranitidine
b. Omeprazole
c. Pantoprazole
d. Lansoprazole

both metabolized by CYP219

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Addition of functional group OH

Hydroxylation

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Enzymes monooxygenase CYP 450 is found in vesicles called

Microsomes

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Cytochromes have the metal complex

Iron

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Drug combines with oxidixed FE3+ form of ion in CYP450 becoming a

binary complex

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NADPH donates electron to the flavoprotein to reduce the oxidized P450 complex by

P450 reductase

Fe 3+ becomes Fe 2+ (reduced)

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A second electron from NADPH will serve to reduce oxygen becoming

activated oxygen-P450 complex

P450Fe2+O2

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P450Fe2+O2 complex transfers oxygen to

the drug metabolized forming an oxidized product + H20 from other O atom

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From CYP450 drug is released in

hydroxylated form | addition of OH

Drug substrates that undergo aromatic hydroxylations

``` Propranolol Phenobarbital Phenytoin Amphetamine Warfarin 17alpha-ethinyl estradiol Napthalene Phenylbutazone Acetalinide Benzpyrene ```

Drug substrates that undergo aliphatic hydroxylations

``` Amobarbital Pentobarbital Secobarbital Chlorpropamide IBUPROFEN meprobamate Glutethimide Phenylbutazone DIGITOXIN ```

Drug that undergoes epoxidation

Aldrin

Drug substrates that undergo N-Dealkylation | O-Dealkylation

``` Morphine Ethylmorphine Benzphetamine Aminopyrine CAFFEINE THEOPHYLLINE CODEINE p-nitroanisole ```

Drug substrates that undergo S-Dealkylation

6-Methylthiopurine | Methitural

The only common structural feature of the wide variety of structurally unrelated drugs and chemicals that serve as subtrates in Phase 1 is their

High lipid solubility

P450s are remarkably

sluggish catalyst | hence need for second phase reactions

Greatest in liver cells and enterocytes

CYP450 Family

CYP450 in the liver is found in the

endoplasmic reticulum

CYP450 in the adrenal gland is found in the

ER | Mitochondria

Main pathway of nicotine metabolism Accounts for 70-80% Coumarin, tobacco nitrosamines Nicotine

Cytochrome 2A6

Nicotine is degraded by C2A6 to

Cotinine | 2’ hydroxynicotine

Cytochrome that metabolizes ``` Diazepam S-mephenytoin Naproxen Nirvanol Omeprazole Clopidogrel Propranolol ```

CYP2C19

Cytochrome that metabolized ``` Warfarin Acetaminophen Caffeine Clomipramine Duloxetene Melatonin Tamoxifen Theophylline ```

CYP1A2

Pharmacologic interaction between omeprazole and clopidogrel leads to

Significantly reduced exposure of active metabolite of clopidogrel Reduction in anticlotting activity of Clopidogrel At risk for stroke and MI bec they utilize the same CYP2C19 pathway

Metabolizes the following drugs Celecoxib Diclofenac Ibuprofen Losartan

CYP2C9

This cytochrome is responsible for over 50% of the prescription drugs metabolized in the liver

Cytochrome 3A4

Which of the following will increase the metabolism of Warfarin? a. Grapefruit juice b. Ketoconazole c. Isoniazid d. Rifampin

Increases the metabolism of drugs on repeated administration Induces P450 by enhancing its synthesis Accelerated substrate mechanism Decreases drug efficacy Dose must be increased

Inducer

OCPs have decreased efficacy with concomittant use of

Rifampin Both decreased efficacy

Benzopyrene (barbecue) induces

Theophylline

Carbamazepine induces

Clonazepam, | Itraconazole

Chlorcyclizine induces

Steroid hormones

Ethchlorvynol induces

Warfarin

Griseofulvin induces

Warfarin

Phenytoin induces

``` Cortisol Dexamethasone Digitoxin Itraconazole Theophylline ```

Rifampin is induces

``` Coumarin Digitoxin Glucocorticoids Itraconazole Methadone Metoprolol OCP Prednisone Propranolol Quinidine Saquinavir ```

Ritonavir is induces

Midazolam

St John’s Wort induces

``` Alprazolam Cyclosporin Digoxin Indinavir OCP Ritonavir Simvastatin Tacrolimus Warfarin ```

A susbtance that binds to CYP450 and decreases its activity Decreased metabolism of the drug Increased drug efficacy Dose must be decreased

Inhibitor

Increases efficacy of valium (diazepam) and may increase its toxic effects inhibitor

Alcohol

Allopurinol Chloramphenicol Isoniazid inhibits

Antipyrene Dicumarol Probenecid Tolbutamide

Chlorpromazine inhibits

Propranolol

Cimetidine inhibits

Chlordiazepoxide Diazepam Warfarin

Dicumarol inhibits

Phenytoin

Disulfiram inhibits

Antipyrine Ethanol Phenytoin Warfarin

Ethanol inhibits

Chlordiazepoxide Diazepam Methanol

Grapefruit juice inhibits

``` Alprazolam Atorvastatin Cisapride Cyclosporine Midazolam Triazolam ```

Itraconazole inhibits

``` Alfentanil Alprazolam Atorvastatin Cyclosporine Diazepam Digoxin ```

OCP inhibit

Antipyrine

Ketoconazole inhibits

Astemizole Cyclosporine Terfenadine

Spironolactone inhibits

Digoxin

Most frequent conjugation reaction of Phase II

Glucoronidation ex. bilirubin

Enzyme responsible for glucoronidation Present in the cytosol and ER

Glucoronosyltransferases

Acetylation involves the enzyme

N-acetyltransferase in cytosol

Acetaminophen undergoes this type of Phase II Conjugation

Glucoronidation ``` Morphine Diazepam N-hydroxydapsone Digitoxin Digoxin ```

Isoniazid Sulfonamide Clonazepam Dapsone undergoes this type of Phase II conjugation

acetylation

Acetaminophen Ethacrynic acid Bromobenzene undergoes this type of Phase II conjugation

Glutathione conjugation

Glutathione conjugation occurs via the enzyme

GSH-S transferase (cytosol, microsome)

Acetaminophen undergoes the ff Phase II reactions

Glucurononidation (95%) Glutathione conjugation (5%) Sulfation (95%)

Dopamine, epinephrine and histsmine undergoes this Phase II conjugation

Methylation by transmethylase SAM

Leukotriene A4 undergoes this type of Phase II conjugation

Water conjugation

Therapeutic dose of Acetaminophen in adult

3 g

When acetaminophen undergoes glutathione conjugation pathway by CYP2E1 and CYP3A4, GSH is depleted faster than it can be regenated and this metabolite accumulates

N-acetylbenzoiminoquinone

If GSH is able to bind to N-acetylbenzoiminoquinone, no toxic metabolite accumulates and this persists instead

Mercapturic acid conjugate

N-acetylbenzoiminoquinone binding with Nucleophilic Cell Macromolecule (Protein-SH) leads to Redox recycling, ROS generation, oxidative stress

Liver cell death

Antidote for paracetamol toxicity in 8-16 hours

N-acetylcysteine

Administration of GSH is not effective in acetaminophen toxicity because

it does not cross cell membranes readily

Bacterially mediated reduction of digoxin | De-glucoronidation of bile

Commensal Gut Microbiota

Charcoal-broiled foods and cruciferous vegetables: induce CYP1A enzymes Grapefruit juice inhibits CYP3 Cigarette smoke: enzyme induction

Diet and environmental factors

Slower metabolism: very young and very old | Young adult male rats metabolize drugs much faster

Age and Sex

Digoxin is reduced in the gut by

Bacteria

Charbroiled foods and cruciferous vegetables induce

CYP1A

Grapefruit inhibits

CYP3A

Cigarette is an enzyme

Inducer

Bound to active site and ER Induce microsomal enzymes

Lipophilic substrates

May enhance also its own metabolism leading to tolerance

Inducer

Some drugs require conjugation with endogenous substrates such as GSH, glucuronic acid or sulfate for their inactivation Faster-reacting drug may effectively deplete endogenous substrate levels

Drug-Endogenous Substance Interactions

Cirrhosis Hepatitis Biliary cirrhosis

Affect drug metabolism | Impair hepatic enzymes and drug elimination

Cardiac disease limits blood flow to liver hence impairs liver metabolism of drugs such as

Lidocaine Isoniazid Morphine

Pulmonary diseases affect drug metabolism as indicated by impaired hydrolysis of and increased half life of

Procainamide Procain Antipyrin in lung cancer

Endocrine dysfunction on drug metabolism Thyroid dysfunction has been associated with altered metabolism of

Digoxin Methimazole Increased half life

Cytokine mediators impair drug metabolism by

inactivating CYP450 | enhancing their degradation

Variant allele of a gene at a population frequency of >/= 1% First drugs -> succinylcholine, INH, warfarin Adverse drug reactions -> dose adjustments needed

Genetic polymorphism

Genetic variants of enzymes in phase I CYP2C19 Individuals with variant allele for CYP2C19 exhibit increased metabolism of Omeprazole and Clopidogrel Increase dose of the drugs

Phase I Polymorphism

Nicotine oxidation is through

CYP2A6 activity

If patient has CYP2A6 polymorphism they are

Less prone to lung cancer even if smoker

Butyrylcholinesterase deficiency (BCHE) Succinylcholine

Phase II Polymorphism

Slow acetylator phenotype NAT2 Common in 50% of blacks Given isoniazid, patient will be prone to developing isoniazid induced periphera neuritis, autoimmune diseases, bladder cancer

Phase II | Polymorphism

UGT Polymorphism UGT1A128 Hyperbilirubinemic diseases (Gilbert’s syndrome) Toxic effects due to impaired drug conjugation or elimination such as irinotectan for patients with cancer

Phase II | Polymorphism

Phase II Polymorphism

Butyrylcholinesterase Slow acetylator Phenotype NAT2 UGT Polymorphism