Drug Biotransformation (Ch 4) Flashcards
biotransformation
termination of activity; drug will either become more or less active
where does biotransformation occur?
liver
GI tract
lungs
skin
kidneys
other tissues
cellular level
list out the pathway of the first pass effect
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)
biotransformation in the liver takes place at the _____
hepatocytes
phase 1 reactions
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
phase 2 reactions
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
specific phase 1 reactions
oxidation
+ cytochrome P450 enzymes
reduction
dehydrogenation
hydrolysis (esters/amides)
list out the generalized cytochrome P450 pathway
- drug (RH) binds to P450[Fe3+]
- FLAVOPROTEIN reduces to its oxidized state and NADPH reduces to oxidized state (NADP+) > this enzymatic process transfers an e- to RH-P450[Fe3+]
- RH-P450[Fe3+] (ferric complex) reduced to RH-P450[Fe2+] (ferrous complex)
- O2 molecule gets attached to RH-P450[Fe2+]
- 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.
- The drug now becomes hydrophilic and can be excreted much easier.
CYP3A4
responsible for 50% of drugs metabolized through phase 1 reactions
CYP2B6
responsible for 8% of drugs that metabolized through phase 1 reactions
CYP2D6
responsible for 20% of drugs metabolized through phase 1 reactions
what does the term “wild-type” mean
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
P450 Induction
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
P450 Inhibition
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
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?
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
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?
since carbamazepine INDUCES 3A4, and 3A4 metabolizes eyrthromycin, the erythryomycin would have LESS effect since it will get metabolized much quicker
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?
warfarin becomes INACTIVATED by CYP1A2, which will be induced by large quantities of cruciferous vegetables
cruciferous veggies induce CYP1A2, which inactivates warfarin
glucuronidation
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
glutathione-s-transferase (GST)
phase II reaction conjugation enzyme
glutathione + xenobiotic > GST > glutathione-s-conjugate
ubiuitous
detoxification
increases water solubility
how are toxic products of metabolism produced?
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
list the tylenol pathway for normal breakdown and toxic byproduct metabolism
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
other factors that impact metabolism
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
what is pharmacogenomics
helps to correlate genetics and drug responses in individuals
why is pharmacogenomics important in personalized medicine?
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
what does it mean to be a “poor metabolizer”
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
codeine (a prodrug) is metabolized by CYP2D6 to morphine; the patient is a PM of CYP2D6. what will the efficacy of this drug be?
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)
omeprazole, an active drug that gets inactivated by CYP2D6, is given to a PM of CYP2D6; what will the efficacy of this drug be?
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
codeine, a prodrug metabolized by CYP2D6 to activate to morphine, is given to ultra-rapid metabolizer; what is the efficacy of this drug?
good efficacy (ultra-rapid metabolizer means prodrug gets rapidly metabolized into active form)
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?
poor efficacy (because the active drug is being ultra-rapidly metabolized into inactive form)
need greater dose or slow release formulation
purine analogs
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
metabolism of 6-MP
- 6-MP + TPMT enzyme > 6-methylmercaptopurine (normal degradation product of 6-MP)
- if pt is TPMT deficient:
+oxidized metabolites OR
+toxic byproducts > 6-thioguanine nucleotides
how do pharmacogenetics play a role in the medication regimen of 6-MP?
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
warfarin characteristics
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
genetic analysis for warfarin
recommended*, not required
reduces 4500 - 22000 serious bleeding events annually
trastuzumab/herceptin genetic testing
HER2/neu overexpression (breast CA)
genetic testing is REQUIRED because herceptin is ONLY USEFUL in HER2+ breast cancer patients
breast cancer and hormone receptors
60-70% of breast cancers express estrogen and progesterone receptors
tx includes estrogen deprivation
ER + tumors respond to tamoxifen/aromatase inhibitors
how does trastuzumab (herceptin) work?
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
