FDN2_SM_WK2_DrugMetabolism Flashcards
Drug Metabolism
What is the purpose of Phase I reactions?
Enzyme ~seduction~
These reactions make the drug more ~alluring~ to phase II enzymes by creating an active site for them
Keep in mind that some drugs are ~pre-lubed~ and do not need to undergo phase I reactions in order to be eliminated
What is the purpose of Phase II reactions?
Phase II reactions make the drug less lipophilic and more polar so it can be excreted
What is the most common pathway for drug elimination?
Phase I: CYP-dependent oxidation via CYP3A4
Phase II: Glucuronidation via UDP Glucuronyl Transfersase (UGT)
Name 3 relevant pro-drugs and describe what happens to them in phase I reactions
Prodrugs undergo bioactivation in phase I rections
Codeine -> Morphine via CYP2D6
Clopidogrel ->>> R-130964 (active form)
via CYP2C19 (rate-limiting enzyme)
Azathioprine ->>> glutathione nucleoties
TPMT facilitates excretion of an intermediate; this is accounted for in dosing.
Name 3 relevant drugs that do not need to undergo Phase I reactions, and explain why
Acetaminophen, Albuteral, Lorazapam
These drugs are ~pre-lubed~ with a group that facilitates Phase II reactions. Interaction with CYPs can create toxic intermediates
What is the only drug (that Silinsky knows of) that is not inactivated by glucuronidation?
Morphine
What drug-metabolizing enzymes are most likely to undergo polymorphisms?
CYP2D6, CYP2C9, CYP2C19
*CYP2D6 is the most common
What drugs are metabolized by CYP2D6?
Drugs for treating CNS disorders (antidepressants, antipsychotics, amphetamines, codeine, opioids)
Beta-Blockers (metroprolol, ___-olol drugs)
What drugs are metabolized by CYP2C9?
Warfarin
NSAIDS (Ibuprofen, Celecoxib)
What drugs are metabolized by CYP2C19?
Diazepam (and other ___-azapam benzos)
Proton-Pump Inhibitors (___-prazoles)
Clopidogrel
Describe the normal metabolism of acetaminophen
Normally, acetaminophen bypasses Phase I metabolism (it is pre-lubed)
It undergoes sulfation or glucuronidation and is safely excreted
If acetaminophen undergoes Phase I reactions via CYP2E1 or CYP3A4, toxic intermediates are created
Why is it a bad idea to take acetaminophen and drink alcohol?
High levels of aclohol induce CYP2E1
When CYP2E1 acts on acetaminophen, the toxic intermediate NAPQI (an evil electrophile) is created.
Under normal circumstances, the hepatocyte can be rescued if GST can conjugate glutathione to NAPQI. However, alcohol also inhibits GST.
What is NAPQI and how is it created?
NAPQI is an evil electrophile, created by Phase I metabolism of acetaminophin by CYP3A4 or CYP2E1
When it interacts with a nucleophilic macromolecule, it causes toxicity and liver cell death.
Conjugating glutathione to NAPQI via GST can create a nontoxic mercapturic acid conjugate that can be excreted
Which CYP causes benzo[a]pyrene to form epoxides? Why do we care about this?
CYP1A causes benzo[a]pyrene to form epoxides
We care becasue epoxides are higly reactive (aka evil). Cigarette smoke and other environmental pollutants contain benzo[a]pyrenes, and they basically cause themselves to become evil by inducing CYP1A
How does Ginkgo influence drug metabolism?
Ginkgo induces CYP2C9, CYP2C19, and CYP3A4
This increases the metabolism of warfarin, celecoxib, and omeprazole.
Incresed warfarin metabolism -> less effective, higher clotting risk
Increased celcoxib metabolism -> less effective pain management
Increased omeprazole metabolism -> less effective PPI activity
How does echinacea influence drug metabolism?
Echinacea inhibits CYP1A2 and induces CYP3A4
This results in:
- Reduced CYP1A2 activity, resulting in less epoxide formation and less toxicity due to environmental pollutants
- Increased metabolism of the many CYP3A4 drugs (this can have mixed effects)
How does St. John’s Wort influence drug metabolism?
Induces CYP3A4 -> mixed results
Induces CYP2C9 -> increased metabolism of warfarin and NSAIDS
Induces CYP2C19 -> increased metabolism of omeprazole, diazepam, clopidogrel
Induces CYP2E1 -> increased toxic metabolites of acetaminophen
Induces CYP3A -> increased metabolism of estrogen (decreased efficacy of oral contraceptives)
You prescribe acetaminophen with codeine to a patient post-op. They call two days later because their pain is poorly controlled. Which cytochrome P450 polymorphism might cause this?
CYP2D6 poor metabolizer
These individuals have imparied conversion of codeine to morphine, with reduced analgesic effects.
Which cytochrome P450 is involved in creating epoxides on benzo[a]pyrene?
CYP1A2
Which cytochrome P450 is involved in the metabolism of 50-60% of clinically prescribed drugs?
CYP3A4
Which cytochrome P450 polymorphism might be associated with needing a lower warfarin dose?
CYP2C9 slow metabolizer
What are the 5 different CYP-dependent Phase I oxidation reactions?
Hydroxylation S-oxidation N-oxidation N-dealkylation O-dealkylation
What are the 2 CYP-independent Phase I oxidations?
Dehydrogenation (pertains to ethanol)
Amine Oxidation
What are the 2 CYP-independent hydroletic Phase I reactions?
Ester Hydrolysis
Epoxide Hydrolases (protects against evil epoxides)
Describe the metabolism of Midazolam
Phase I: oxidation (N-dealkylation) mediated by CYP3A4
Phase II: Glucuronidation mediated by UGT
(They typical drug metabolism pathway; this applies to all _____-azolam benzodiazepine drugs)
What is something you need to keep in mind when prescribing the H2 histamine receptor blocker cimetidine?
Cimetidine inhibits all CYPs except CYP2E1;
This creates the potential for adverse drug interatctions
- Inability to activate a pro-drug, resulting in a reduced effect
- Inability to excrete a standard drug, resulting in an increased effect or toxicity
What are two examples of Methylxanthines?
What is their mechanism of action?
Caffeine and theophylline (treats respiratory diseases) are both methylxanthines
They are competitive inhibitors of adenosine (adenosine ususally inhibits cell function)
What are the 5 Phase II metabolism reactions?
SAGGMeth
Sulfation
Acetylation
Glucuronidation
Glutathione conjugation
Methylation
What is the role of glutathione in acetaminophen metabolism?
Glutathione conjugation (mediated by GST) can “rescue” hepatocytes from the toxic intermediate NAPQI.
NAPQI is created by CYP3A4 and CYP2E1.
If it is conjugated to glutathione, it can be safely excreted.
If instead it interacts with a nucleophilic macromolecule, it can lead to toxicity and hepatocyte death
Which cytochrome P450 polymorphism is associated with impaired metabolism of Proton-Pump Inhibitors?
CYP2C19 slow metabolizer
Which cytochrome P450 is associated with the creation of the two active metabolizes of Diazepam?
CYP2C19
Which cytochrome P450 polymorphism is associated with a necessary increased dose of Metroprolol (A Beta1 blocker)
CYP2D6 ultrarapid metabolizer
Why does CYP3A4 have such a broad substrate specificity?
CYP3A4 has a large active site cavity volume. It can bind to substrates of a wide variety of shapes and sizes
Which cytochrome P450 is associated with caffeine and theophyline metabolism?
CYP1A2
Which cytochrome P450 is involved in creating toxic intermediates in acetaminophin metabolism?
CYP3A4 and CYP2E1
List some relevant actions of the CYP1As
CYP1A2: Phase I metabolism of methylxanthines (caffeine and theophyline)
CYP1A?: Causes environmental pollutants containing benzo[a]pyrene to become toxic
What are the three major processes in renal exretion of drugs?
Glomerular filtration, tubular secretion, passive tubular reabsorption
Describe glomerular filtration
As blood rushes through the glomerulus, filtrate enters the kidney through the glomerulus
The three layers that make up the glomerular filtration barrier determine what enters the filtrate, and what stays in the blood.
Small particles that are not bound to blasma proteins can easily enter the firltrate.
Describe the Glomerular Filtration Barrier
The three membrane layers that achieve a size- and charge-sensitive filtration of drugs and solutes in the glomerulus.
- Glomerular capilary endothelum
- Porous glomerular basement membrane
- Podocytes
These membranes contain fenestrae and negatively charged glycoproteins. The result is that negatively charged plasma proteins cannot enter (among other things)
Describe tubular secretion
In tubular secretion, ionized drugs are secreted into the filtrate from the bloodstream.
This process is driven by transporters
- SLC22 transporters uptake molecules from the capilaries into the tubular endothelium
- SLC and ABC transporters promote the efflux of molecules from the endothelium to the limunal spacs
What transporters are involved in tubular secretion?
SLC: Organic Anion Transporters and Organic Cation Transporters
ABC: P-glycoprotein and MRP1
What transporters are located on the basolateral side of the renal proximal tubule?
SLC transporters. This is the side that faces the capilaries
- OATs and OCTs uptake anions and cations into the tubular endothelium
What transporters are located on the aplical side of the renal proximal tubule?
SLC: OATs and OCTs
ABC: P-glycoprotein, MRP1
Together, these transporters move substances from the tubular endothelium into the lumen of the proximal tubule
How would you promote the excretion of a weakly basic drug?
Basic drugs are charged in their protonated form.
If the pH of urine
To promote the excretion of a basic drug, make the urine more acidic
Describe passive tubular reabsorption
Drugs and solutes are reabsorbed into the systemic circulation from the renal tubule.
Nonionized, lipid soluble forms of the drug are able to pass back into the interstitium
Changing the pH of the urine can promote the retention or excrection of acidic or basic drugs
How would you promote the excretion of a weakly acidic drug?
Acidic drugs are charged in their deprotonated form
If pH of urine > pKa of the drug, the ionized form will dominate, and the drug will not be reabsorbed
To promote the excretion of an acidic drug, make the urine more basic
In what scenarios would you want to promote excretion of a drug?
Overdose or toxicity due to high drug concentration
Drug excretion via bile is analogous to what step in renal excretion?
Proximal tubular secretion
Both involve ABC and SLC transporters
What transporters are invovled in dug excretion through the bile?
SLC: OAT and OCT transporters
ABCs
These transporters exist in canalicular membranes of hepatocyctes to secrete drugs into the bile
A defect in which hepatocyte transporter is implicated in elevated cholesterol and phytoserol?
ABCG5/8
A defect in which hepatocyte transporters is implicated in risk for myotoxicity with the use of statins?
SLCO1B1; Defects in this transporter result in imparied secretion of the drug into the bile
This results decreased excretion and increased plasma concentrations of the drug, which can lead to myotoxicity
What kinds of drugs are most likely to be excreted in the bile?
Heavy drugs; molecular weight >300
Describe enterohepatic circulation
A recycling system!
Drugs that are glucuronidated in the liver are secreted into the bile and then dumped into the gut
Bacteria in the colon may cleave the glucuronide off of the drug, increasing its lipophilicity
The drug is now more likely to be reabsorbed into the hepatic circulation
Why do some antibiotics (espcially rifampin) interfere with drug efficacy?
Antibiotics may disrupt the bacteria in the colon
The bacteria normally cleave glucuronide off of the drug, allowing the drug to be reabsorbed into the circulation.
If the bacteria are dead, more of the drug will be excreted, lowering the expected plasma concentration of the drug and reducing its efficacy
For a drug that is excreted via glomerular filtration, how would you adjust dosing for a patient with renal failure?
You would want to lower the dosage of the drug; less will be filtered into the kidney, which means that more will remain in the plasma.
Lowering the dosage can reduce the risk of toxicity
What factors impact the clearance of “high extraction drugs?”
Clearance depends on blood flow to the liver
Metabolism is not rate-limiting, and plasma-protein binding doesn’t really matter
Note: These drugs tend to have high first-pass metabolism
What is the equation for hepatic clearance?
CL = (Rate of elimination) /[plasma concentration]
What factors impact the clearance of “low extraction drugs?”
Hepatic metabolism and plasma protein binding
Blood flow to the liver is not rate limiting, because metabolism in the liver is slower, and dependent on the fraction of free drug in the blood (which is impacted by binding to plasma proteins)
What are some examples of high extraction drugs?
Morphine, propanolol, lidocaine
What are some examples of low extraction drugs?
Digoxin, diazepam, phenytoin, valproic acid, cimetidine
(DDPVC)
How does binding to plasma proteins affect renal excretion of drugs?
More binding to proteins = less excretion
Bound proteins cannot enter glomerular filtrate
What is the differnece between pharmacogenetics and pharmacogenomcis?
Both are related to the study of genes
Pharmacogenetics looks at individuals or families, and how their SNPs may affect drug response
Pharmacogenomics looks at genes that are associated with differential drug responses among groups of unrelated indivdiuals, on a population-wide level
List a few specific pharmacogenetic or pharmacogenomic syndromes
Malignant hyperthermia susceptibility
G-6-P dehydrogenase deficiency
Pseudocholinesterase deficiency
Describe the relevant pharmacogenomics of codeine
Codeine is a prodrug that requires converstion to morphine by CYP2D6
CYP2D6 ultrarapid metabolizers end up making a lot of morphine. This can lead to a dangerous functional morphine oversdose (increased sedation, respiratory depression)
CYP2D6 poor metabolizers have lower than expected analgesic effects from codeine
Describe the relevant pharmacogenomics of clopidogrel
Clopidogrel is a pro-drug that is prescribed as an anti-platelet agent. CYP2C19 is required to activate the drug.
CYP2C19 ultrarapid metabolizeers are at an increased risk for bleeding
CYP2C19 poor metabolizers do not have adequate antiplatelet effects; they are at an increased risk for blood clots
Which cytochrome P450 is relevant to codeine metabolism?
CYP2D6 activates codine to morphine
Which cytochrome P450 is relevant to colpidogrel metabolism?
CYP2C19 activates clopidogrel
Which cytochrome P450 is relevant to Omeprazole (and other ___-prazole) metabolism?
CYP2C19 and CYP3A4 facilitate excretion of omeprazole
Which enzyme is relevant to Thiopurine drug metabolism? (ex: Azathiopurine)
Thiopurine S-Methyltransferase; required for excretion of the drug
Which cytochrome P450 is relevant to warfarin metabolism?
CYP2C9 facilitates excretion of warfarin
Describe the relevant pharmacogenomics of Omeprazole (and other ___ -azole drugs)
____-prazole drugs are proton pump inhibitors. CYP2C19 and CYP3A4 are required for metabilism and
CYP2C19 ultrarapid metabolizers clear the drug too quickly, resulting in poor treatment of gastric acidity
CYP2C19 poor metabolizers experience a higher efficacy of PPI drugs, but in children this may be associated with upper respiratory infections and strep
Describe the relevant pharmacogenomics of Thiopurine drugs
Thiopurine drugs like Azathioprine are pro-drugs that are used to treat leukemia, rehumatic disease, IBD, and organ transplantation. They are activated by a metabolic pathway to glutathione nucleotides
Thiopurine S-Methyltransferase (TPMT) facilitates the excretion of an intermediate of the pathway, 6-mercaptopurine. If there is a loss of function/reduced function mutation in the TPMT gene, more glutathione nucleotides will be made.
This results in increased drug efficacy, but also risk for toxic effects
What are Thiopurine drugs used for?
Thiopurine drugs are used to treat leukemia, IBD, rheumatic disease, and organ transplant
(Think Autoimmune disorders)
Give some examples of Thiopurine drugs
Azathioprine, 6-mercaptopurine, and 6-thioguanin
Describe the relevant pharmacogenomics of warfarin
Warfarin is an anticoagulent that is metabolized by CYP2C9.
CYP2C9 ultrarapid metabolizers will clear the drug quickly, putting the patient at risk for clotting
CYP2C9 poor metabolizers will clear the drug slowly, resulting in higher plasma concentration and risk for bleeding
Warfarin exerts its effects by inhibiting VKORC1, an endogenous enzyme required for sythesis of clotting factors
LOF mutations in VKORCI result in increased baseline INR (it takes longer for the patient to clot, putting them at increased risk for bleeding)
What enzyme is relevant to warfarin pharmacokinetics?
CYP2C9
What enzyeme is relevant to Warfarin pharmacodynamics?
VKORCI
Describe a relevant exmample of somatic pharmacogenomics
Tumors may contain genetic variants that make them more or less responsive to anti-cancer drugs
Hyperactive EGF Receptors: This drug will respond really well to anti-cancer drugs that target the EGF receptor
Nonresponsive EGF Receptors: If anti-cancer drugs work to eradicate 99% of tumor cells, the ones that remain are likely resistant to the drugs due to a mutation that gives them resistance to the drug. Relapse due to growth of these resistant cells is hard to treat, because they are unresponsive to the anti-cancer drug.
What are the “good and the bad” of gultathione?
Good: Glutathione conjugation via GST can protect against toxic metabolites and therefore prevent cancers from developing
Bad: If cancer does develop, high levels of GST in tumors can cause cancer cell proliferation and resistance to chemotherapy
How would drinking grapefruit juice affect a patient taking statin drugs?
Grapefruit juice inhibits CYP3A4, resulting in slower metabolism of the drug. The effects of the statin will be potentiated.
Suppose you get blackout drunk at a party and your “friend” gives you acetaminophen.
You are worried about the toxic effects that NAPQI may have on your system.
Luckily, you are a medical studnet and have free access to any chemical in the world. What antidote do you give yourself?
N-Acetylcysteine (NAC)
NAC conjugates directly with NAPQI, replaces glutathione stores, and can protect against extrahepatic injury
Giving extra glutathione may seem like it could work, but it would be ineffective because it can’t cross cell membranes.
How would you interpret the genotype CYP2D6*1x3
The individual has an extra functional copy of the reference CYP2D6 gene; they may have increased CYP2D6 activity
What is the equation for volume of distribution (Vd)?
Vd = (dose)/(plasma concentration)
Unit = L
What does the volume of distribution (Vd) represent?
The amount of the administered drug that is in tissues, organs, or otherwise sequestered out of the systemic circulation.
This measurement is only meaningful right after the drug has been distributed (before it is metabolized or excreted)
What factors affect Volume of Distribution (Vd)?
Patient factors: age, gender, body muscle/fat proportion, level of hydration, water distribution (pregnancy, edema)
Drug Factors: High lipid solubility, low ionization = higher Vd
Vd is unaffected by half-life or clearance
What is the equation for half-life of a drug?
For first order drugs t1/2= 0.693*Vd/Cl
For zero-order drugs, half life cannot be calculated by a simple equation; the time it takes for 50% of the drug to be eliminated will depend on how much drug is in the system
What is the equation for Clearance (CL)?
CL = (rate of elimination)/(plasma concentration of the drug)
Unit: L/hr or mL/min
CL is constant for first order drugs; the rate of elimination increases or decreases with the [drug]
CL is not constant for zero order drugs
What does the Clearance (CL) of a drug mean?
The volume of plasma cleared of the drug per unit time.
What is the equation for rate of elimination?
Rate of Elimination = CL * [drug in plasma]
How is Rate of Elimination different for zero order and first order drugs?
First order drugs: Rate of Elimination is a fixed fraction of the [drug]; this is not a saturated system, and can change based on the [drug]
Zero order drugs: Rate of Elimination is a fixed amount of drug. It doesn’t depend on the [drug]; think of it like a saturated system that is going as fast as it can
What is the equation for steady state concentration (Css)?
For IV drugs: (infusion rate)/(CL)
For oral drugs: (Oral dose)/(dosing interval * CL)
If you are administering a constand dose, about how long will it take a patient to reach Css?
~3.3 half-lives to reach 90% Css (which is pretty much the goal)
What is the equation for loading dose (LD)?
LD = Css * Vd
What does it mean if a drug has a high Vd?
A high Vd means that a large amount of the drug gets sequestered in tissues or other spaces outside of the systemic circulation
If a drug has a low Vd, how is the Css affected?
It isn’t; Css doesn’t depend on Vd
Css = Infusion rate/CL
The goal for Css is to have a steady [drug] in the systemic circulation. After a drug has been distributed to tissues and other spaces outside of the systemic circulation, it kind of just stays there and doesn’t affect [drug}
What is the equation for maintenence dose?
IV drug: I = Css * CL
What kind of transporter is p-glycoprotein?
ATP Binding Cassette
(Directly energy dependent = Involved in active transport)
Which genotypes of CYP2D6 would result in ultrarapid metabolism?
More than 2 copies of *1 or *2
Which genotypes of CYP2D6 would result in poor metabolism?
Two copies of anything that isn’t *1 or *2
*1 or *2 plus any other allele = within normal range
(*4 and *5 are most common)
Which genotypes of CYP2C19 would result in ultrarapid metabolism?
*1/*17 or *17/*17 (17 is ultrarapid)
Which genotypes of CYP2C19 would result in poor metabolism?
Any genotype that doesn’t contain *1 or *17
(*2 and *3 are common)
In which populations are CYP2D6 poor metabolizers most common?
Caucasians (8-10%)
African Americans (1-3%)
In which populations are CYP2D6 ultrarapid metabolizers most common?
Ethiopians and Saudi Arabians (30%)
In which populations are CYP2C19 poor metabolizers most common?
Asians (15-20%)
Caucasians (3-5%)
African Americans (3-5%)
In which populations are CYP2C9 poor metabolizers most common?
Caucasians (10-35%)
