Biotransformation

Question 1

Importance of biotransformation

Answer 1

The processing of xenobiotics for elimination- xenobiotics are foreign compounds including environmental chemicals, food toxins, therapeutic drugs, and recreational drugs

Question 2

Hydrophilic drugs

Answer 2

Polar, ionize in physiological pH, easily excreted, low therapeutic effectiveness, short half-life

Question 3

Lipophilic drugs

Answer 3

Most drugs, can cross membranes to get to site of action, difficult to eliminate, must be processed to prevent toxicity

Question 4

Functions of biotransformation

Answer 4

Metabolize, detoxify, and render drug less toxic (metabolism)
Eliminate the drug from the body (disposition)

Question 5

Phases of biotransformation

Answer 5

Phase I- metabolism and detoxification

Phase II- elimination, makes drug more excretable

Question 6

Most important cytochrome P450 families

Answer 6

CYP1, CYP2, CYP3, CYP4

Question 7

Important CYP enzymes

Answer 7

CYP3A4- responsible for >50% of prescription drug metabolism, CYP2D6, CYP2C, CYP1A2, CYP2E1

Question 8

Induction

Answer 8

Transcriptional activation of the enzyme

Question 9

Tobacco smoke, charcoal broiled meat

Answer 9

Induces CYP1A

Question 10

Barbiturates (anxiolytics)

Answer 10

Induces CYP2B1

Question 11

Ethanol

Answer 11

Induces CYP2E1

Question 12

Steroids

Answer 12

Induces CYP3A4

Question 13

Fibrates (LDL lowering drugs)

Answer 13

Induces CYP4A

Question 14

Cimetidine (gastric ulcer medication)

Answer 14

Inhibitor, binds tightly to heme and reduces metabolism of endogenous substrates

Question 15

Ketoconazole (anti-fungal medication)

Answer 15

Inhibitor, binds tightly to heme and reduces metabolism of endogenous substrates

Question 16

Macrolides (antibacterial)

Answer 16

Inhibitor, metabolized to reactive species, complex with heme iron and rend it catalytically inactive

Question 17

Suicide inhibitors

Answer 17

Irreversibly inhibit CYP via covalent binding to the heme or protein portion of the enzyme

Question 18

Phase I

Answer 18

Enzymes add polar group onto the drug to make it more polar (hydrophilic), allowing it to be conjugated, includes: oxidation, reduction, and hydrolysis reactions

Question 19

Phase I enzymes

Answer 19

Most are heme protein mono-oxygenases of cytochrome P450 gene family

Question 20

Phase II

Answer 20

Drugs that have undergone phase I may have chemical groups that allow them to conjugate with endogenous substances, conjugates are polar, often inactive, and readily excreted

Question 21

Consequences of conjugation reactions

Answer 21

May lead to formation of reactive species responsible for drug toxicity

Question 22

Acetaminophen processing

Answer 22

95% goes through conjugation- glucuronidation, sulfation

5% goes through P450 metabolism- makes reactive agent NAPQI, GSH conjugates NAPQI for excretion

Question 23

Acetaminophen overdose

Answer 23

Conjugation reaction is saturated, more goes through P450 and saturates GSH conjugation, NAPQI accumulates, forms protein adducts in liver, hepatic necrosis, death

Question 24

Alcoholics and acetaminophen OD

Answer 24

More susceptible because ethanol induces the same P450 and shifts reaction of the drug to P450 metabolism

Question 25

Treating acetaminophen OD

Answer 25

Give N-acetylcysteine (NAC), provides SH group to bind toxic protein, creates cysteine conjugate for excretion, must give NAC within 8-16 hours

Question 26

2D6 polymorphism, PM phenotype

Answer 26

Associated with breast cancer relapse in those treated with tamoxifen, dependent on 2D6 metabolism

Question 27

2D6 polymorphism, UM phenotype

Answer 27

Displays in 1/3 of Ethiopians and Saudi Arabians, patients require 2-3x dose of nortriptyline (antidepressant), poor response correlates with higher suicide rates, prodrug codeine is metabolized faster to morphine, faster sedation

Question 28

2C19 polymorphism, PM phenotype

Answer 28

Poor metabolizer, occurs in 3-5% of Caucasians, 18-23% of Japanese, lack hydroxylation activity and S- and R-forms of mephenytoin accumulate, cause sedation and ataxia

Question 29

2C19 polymorphism, EM phenotype

Answer 29

Extensive metabolizer, S-form is hydroxylated by 2C19, conjugated by glucuronidation, excreted into urine, R-form is slowly demethylated into active nirvanol

Question 30

2C9 polymorphism

Answer 30

Impaired formation or inactive protein, occurs in 6-13% of Caucasians, increases patient sensitivity to warfarin, can lead to excessive bleeding and death

Question 31

Warfarin

Answer 31

Inhibits vitamin K epoxide reductase- required for recycling vitamin K which is crucial in activation of clotting factors, warfarin inhibits clotting

Question 32

Slow acetylators

Answer 32

Occur in 50% of Whites and Blacks, associated with higher incidence of isoniazid-induced peripheral neuritis, autoimmune disorders, bladder cancer

Question 33

Newborn child biotransformation

Answer 33

Capable of carrying out many, but not all biotransformation reactions

Question 34

Gray baby syndrome

Answer 34

Chloramphenicol (antibacterial) excretion requires oxidative transformation followed by conjugation, oxidative metabolite is toxic, can accumulate if not conjugated (newborns)

Question 35

Elderly biotransformation

Answer 35

Reduced metabolic capacity due to decline in liver mass, hepatic blood flow, reduced renal function, some take multiple medications that can contribute to drug-drug interactions

Question 36

Androgenic hormone levels

Answer 36

Associated with sex-dependent differences in drug metabolism

Question 37

Diet and environment

Answer 37

May alter biotransformation by inducing or inhibiting P450 enzymes

Question 38

Grapefruit juice

Answer 38

Inhibits CYP3A4

Question 39

St. John's wart

Answer 39

Herbal medication for mood stabilization, induces CYP3A4

Question 40

Polycyclic aromatic hydrocarbons in cigarette smoke

Answer 40

Induces CYP1A1, CYP1A2, CYP2E1

Question 41

Lead

Answer 41

Induces heme-oxygenase enzyme, breaks down P450

Question 42

Drug-drug interactions, two drugs metabolized by the same enzyme

Answer 42

The drug with lower affinity accumulates and becomes toxic

Question 43

Drug-drug interactions, one drug induces the enzyme

Answer 43

Can increase or decrease the efficacy of the other drug

Question 44

Drug-drug interactions, one drug inhibits the enzyme

Answer 44

Reduces the metabolism of the other drug

Question 45

Rifampin (antibacterial) drug-drug interaction

Answer 45

Induces CYP3A4, increases the metabolism of estrogenic component of estrogen-based contraception

Question 46

Erythromycin (macrolide antibiotic) drug-drug interaction

Answer 46

Metabolized by CYP3A4, metabolite complexes with 3A4 and inhibits the enzyme, inhibits 3A4 metabolism of other drugs

Question 47

Methanol intoxication drug-drug interaction

Answer 47

Intoxication results in blindness/death due to toxicity of formaldehyde metabolite, ethanol competes with methanol for oxidation by alcohol dehydrogenase, delayed methanol oxidation reduces metabolite formation, allows time for renal excretion

Question 48

Liver diseases and biotransformation

Answer 48

Main site of biotransformation, liver diseases (hepatitis, cirrhosis, cancer) will decrease enzymes required for metabolism

Question 49

Cardiac diseases and biotransformation

Answer 49

Can compromise blood flow, reduce drug delivery to the heart for effect, reduce drug delivery to the liver for metabolism

Question 50

Thyroid diseases and biotransformation

Answer 50

Thyroid hormone regulates rate of metabolism, hyperthyroidism increases drug metabolism, hypothyroidism decreases drug metabolism

Question 51

Kidney diseases and biotransformation

Answer 51

Decreases drug excretion