Drug Biotransformation (Ch 4)

Question 1

biotransformation

Answer 1

termination of activity; drug will either become more or less active

Question 2

where does biotransformation occur?

Answer 2

liver
GI tract
lungs
skin
kidneys
other tissues
cellular level

Question 3

list out the pathway of the first pass effect

Answer 3

ORAL:
1. intestines
2. capillary bed
3. hepatic portal vein
4. sinusoids
5. hepatic vein
6. vena cava
7. systemic circulation
8. (IV: hepatic artery > sinusoids > hepatic vein > vena cava > back to systemic circ)

Question 4

biotransformation in the liver takes place at the _____

Answer 4

hepatocytes

Question 5

phase 1 reactions

Answer 5

convert the drug to more polar metabolite

+ adds or unmasks functional group (-OH, -NH, -SH etc.)
+ oxidation (CYP450), reduction, dehydrogenation, hydrolysis (esters, amides)
+ most drugs inactivated
+ more readily excreted (lipophilic becomes hydrophilic)

hydrophilic drugs will get excreted more easily

Question 6

phase 2 reactions

Answer 6

conjugation to endogenous substrate
results in higher molecular weight compounds - often detoxifying

+glucuronidation - adds UDP glucuronic acid
+glutathione - adds GSH (glutathione)
+sulfation - adds phosphoadenosyl/phosphosulfate
+methylation - adds S-adenosylmethionine

Question 7

specific phase 1 reactions

Answer 7

oxidation
+ cytochrome P450 enzymes
reduction
dehydrogenation
hydrolysis (esters/amides)

Question 8

list out the generalized cytochrome P450 pathway

Answer 8

1. drug (RH) binds to P450[Fe³⁺]
2. FLAVOPROTEIN reduces to its oxidized state and NADPH reduces to oxidized state (NADP+) > this enzymatic process transfers an e- to RH-P450[Fe³⁺]
3. RH-P450[Fe³⁺] (ferric complex) reduced to RH-P450[Fe²⁺] (ferrous complex)
4. O₂ molecule gets attached to RH-P450[Fe²⁺]
5. The oxygen molecule now gets hydrolyzed by two protons (2H+) to make water and the remaining oxygen gets turned into a hydroxyl group bound on the drug.
6. The drug now becomes hydrophilic and can be excreted much easier.

Question 9

CYP3A4

Answer 9

responsible for 50% of drugs metabolized through phase 1 reactions

Question 10

CYP2B6

Answer 10

responsible for 8% of drugs that metabolized through phase 1 reactions

Question 11

CYP2D6

Answer 11

responsible for 20% of drugs metabolized through phase 1 reactions

Question 12

what does the term “wild-type” mean

Answer 12

this variation occurs most often in the population

ex) CYP3A4 * 1 is the wild type and
CYP3A4 * 2 is a mutant from the wild type

Question 13

P450 Induction

Answer 13

a substance INDUCES P450 enzyme (P450 levels are INCREASED)
this may cause:
+a drug to become inactivated much more QUICKLY
+a prodrug to become activated much more QUICKLY

problems include: toxicity

Question 14

P450 Inhibition

Answer 14

a substance INHIBITS P450 enzyme (P450 levels are DECREASED)
this may cause:
+a drug to become inactivated much more SLOWLY
+a prodrug to become activated much more SLOWLY

problems include: toxicity; less effective drugs

Question 15

your patient is on clopidogrel for previous stents but you need to sedate them with propofol; propofol is normally metabolized by CYP2B6

clopidogrel inhibits CYP2B6; what would you anticipate happens with this patient?

Answer 15

clopidogrel is an inhibitor of 2B6
your patient would be hard to arouse since propofol would be lingering in the body
this happens because CYP2B6 normally metabolizes propofol; therefore, since clopidogrel inhibits metabolism of prpofol by 2B6, propofol will stay in the body longer than normal

Question 16

your patient is on carbamazepine for seizures and you need to administer their erythryomycin (which is metabolized by CYP3A4); carbamazepine is a 3A4 inducer. what would you expect to happen with this patient?

Answer 16

since carbamazepine INDUCES 3A4, and 3A4 metabolizes eyrthromycin, the erythryomycin would have LESS effect since it will get metabolized much quicker

Question 17

cruciferous vegetables are inducers of CYP1A2 and you ingest massive quantities. you are also put on warfarin for clotting (which is inactivated by CYP1A2). what will the drug interaction be?

Answer 17

warfarin becomes INACTIVATED by CYP1A2, which will be induced by large quantities of cruciferous vegetables

cruciferous veggies induce CYP1A2, which inactivates warfarin

Question 18

glucuronidation

Answer 18

phase II reaction conjugation rxn

uridine diphosphate glucuronyltransferase (UGT) attaches glucuronic acid to substrate group (i.e. phenol, alcohol, carboxyl, sulfhydryl)

primarily in liver

increases aqueous solubility of drug to increase urinary excretion of drug

ex) codeine (a pro-drug) that is activated by CYP2D6 turns into morphine, but is inactivated by UGT2B7 into morphine-6-glucuronide

Question 19

glutathione-s-transferase (GST)

Answer 19

phase II reaction conjugation enzyme

glutathione + xenobiotic > GST > glutathione-s-conjugate

ubiuitous
detoxification
increases water solubility

Question 20

how are toxic products of metabolism produced?

Answer 20

therapeutic doses go through the normal detox pathway

if there is overdose, normal pathways are overwhelmed and alternate pathways are activated – toxic byproducts produced

ex) tylenol

Question 21

list the tylenol pathway for normal breakdown and toxic byproduct metabolism

Answer 21

normal breakdown pathway:
tylenol
1. glucuronidation
2. sulfation
will get detoxed into a form that can be excreted

toxic metabolism pathway//OD on tylenol:
1. CYP2E1
2. CYP3A4
reactive toxic intermediates
1. back up pathway to excrete (via glutathione conjugation)
+mercapturic acid conjugate excreted
+mucomyst can work here to recycle glutathione
2. nucleophillic cell macromolecules (protein-SH)
+leads to liver cell death

Question 22

other factors that impact metabolism

Answer 22

plasma - cholinesterase
intestine (has less hepatic enzymes than liver)
kidneys (P450s, GSTs, important for volatile anesthetics)
brain - p450s, psychotropic metabolites
lungs - phase I/II
diet - charcoal broiling (induce CYP1A), grapefruit juice (inhibits CYP3A)
environment (smoking)
age/sex - males faster than females, pre vs post-pubescent
disease state
genetics

Question 23

what is pharmacogenomics

Answer 23

helps to correlate genetics and drug responses in individuals

Question 24

why is pharmacogenomics important in personalized medicine?

Answer 24

genetics can help to predict and correlate drug response in the indivualized patient – this can be done to help predict and explain a medication regimen (side effects, efficacy, etc.) to the patient before they even take it

Question 25

what does it mean to be a "poor metabolizer"

Answer 25

the individual has the "poor metabolizer" phenotype in their genetics usually due to some mutation in their genetic sequence (SNP - single nucleotide polymorphism) they have SNP that makes an **enzyme less active**

Question 26

codeine (a prodrug) is metabolized by CYP2D6 to morphine; the patient is a PM of CYP2D6. what will the efficacy of this drug be?

Answer 26

codeine will have a **poor efficacy** (if they are a PM, the CYP2D6 will be LESS ACTIVE) they will possible accumulate the prodrug (because codeine is not being metabolized as quickly)

Question 27

omeprazole, an active drug that gets inactivated by CYP2D6, is given to a PM of CYP2D6; what will the efficacy of this drug be?

Answer 27

good efficacy -- the drug is active and won't be broken down as fast by CYP2D6 (since the patient is a PM, CYP2D6 is LESS ACTIVE and breaking down the active drug less) they can accumulate active drug and can produce adverse reactions may need a lower dose

Question 28

codeine, a prodrug metabolized by CYP2D6 to activate to morphine, is given to ultra-rapid metabolizer; what is the efficacy of this drug?

Answer 28

good efficacy (ultra-rapid metabolizer means prodrug gets rapidly metabolized into active form)

Question 29

omeprazole (an active drug) gets inactivated by CYP2D6 metabolism; this drug is given to an ultra-rapid metabolizer. what is the efficacy of this drug?

Answer 29

poor efficacy (because the active drug is being ultra-rapidly metabolized into inactive form) need greater dose or slow release formulation

Question 30

purine analogs

Answer 30

purines (adenine and guanine -- two nitrogenous bases in DNA) ex) **6-mercaptopurine, 6-thioguanine, and azathioprine** interferes with **nucleic acid synthesis**; **blocks rapidly dividing cells from dividing** used to treat lymphoblastic leukemia, autoimmune disease, IBD, and s/p transplant therapeutic index limited by myelosuppression

Question 31

metabolism of 6-MP

Answer 31

1. 6-MP + TPMT enzyme > 6-**methyl**mercaptopurine (normal degradation product of 6-MP) 2. if pt is TPMT deficient: +oxidized metabolites OR +toxic byproducts > 6-thioguanine nucleotides

Question 32

how do pharmacogenetics play a role in the medication regimen of 6-MP?

Answer 32

most people metabolize the drug *quickly*; dose needs to be high enough to treat leukemia and prevent relapses others metabolize the drug SLOWLY; needs lower doses to avoid toxic SE a small portion of people are poor metabolizers, so effects can be fatal fo these patients there is a diversity in responses d/t variations in genetic profiles; **screening MUST be done prior to giving 6-MP** to avoid death

Question 33

warfarin characteristics

Answer 33

primary drug responsible for causing adverse events major bleeding ranging from 2-16%; ranks amongst the top drugs associated with ER vists for bleeding more than half of the population needs dose adjustments while on warfarin (55% need less than 5mg dosing; 33% need more than 5mg) racemix mixture +**S-warfarin is 7-10x more potent than R** +if pt is ultra rapid metabolizer of S-warfarin, they're left with R-warfarin which is **not as potent**

Question 34

genetic analysis for warfarin

Answer 34

recommended*, not required reduces 4500 - 22000 serious bleeding events annually

Question 35

trastuzumab/herceptin genetic testing

Answer 35

HER2/neu overexpression (breast CA) genetic testing is REQUIRED because herceptin is **ONLY USEFUL in HER2+ breast cancer patients**

Question 36

breast cancer and hormone receptors

Answer 36

60-70% of breast cancers express estrogen and progesterone receptors tx includes **estrogen deprivation** ER + tumors respond to tamoxifen/aromatase inhibitors

Question 37

how does trastuzumab (herceptin) work?

Answer 37

normal cells have 1 copy of HER2 on each **chromosome 17** in breast CA (15-25%), HER2 is amplified 2-20x, generating up to 100x normal receptors on cell surface **herceptin is a MAB, so the antibodies bind and shut down receptors -- but only useful in HER2+ breast cancers**