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MEDCHEM 570 > Midterm 1 > Flashcards

Midterm 1 Flashcards

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1
Q

Drug Metabolism

A

The process of enzymatic biotransformation of drugs.

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2
Q

Why is it beneficial to have a parent drug metabolized to multiple metabolites?

A

Reduces the likelihood that a metabolite will be toxic.

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3
Q

Enterocytes

A

The cells that line the intestinal lumen. They have families of drug transporters and drug metabolising enzymes that act to promote or reduce absorption of a given drug into the portal circulation.

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4
Q

Describe the route of an orally administered drug to get to the systemic circulation.

A
  1. Drug is absorbed through cells lining the small intestine or stomach. Enterocytes (lining intestinal lumen) transport or metabolize drugs. 2. drug enters the liver through the portal vein. 3. drug exits the liver into the systemic blood circulation.
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5
Q

Define Pre-Systemic Metabolism

A

Also referred to as the first-pass effect. Metabolism of the drug by enzymes in the enterocytes or hepatocytes before it can enter the systemic circulation and travel to the site of action.

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6
Q

Define bioavailability

A

The fraction of an oral dose that reaches the systemic circulation.

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7
Q

Explain why we want to avoid first pass metabolism.

A
  1. leads to high interindividual variabilit in blood levels of drug. 2. leads to an exaggerated sensitivity to drug-drug interactions.
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8
Q

Describe Central Vein

A

Where the drug (or metabolite if drug was metabolized in liver) exit the liver and go into the systemic circulation.

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9
Q

Define Hepatic Clearance

A

Refers to when a drug is converted to a metabolite in the liver. Bile Canaliculus and hepatic vein are the two ways a drug and its metabolite can exit the liver.

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10
Q

Define Bile Canaliculus

A

hepatocytes are always bordered by a bile canaliculus. These are responsible for transporting molecules that enter back in the GI tract for excretion into the feces. Is a very selective process.

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11
Q

What are Phase II reactions?

A

generate highly polar derivatives known as conjugates of drugs and metabolites of drugs. combined in covalent reactions with endogenous hydrophilic compounds. There are three kinds: glucuronidation, SULTs, and GSH conjugation to mercapturic acid formation.

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12
Q

Glucuronidation.

A

microsomal enzyme. polar group on drug/metabolite + UDPGA –> glucuronidated drug/metabolite + UDPG. UDPGA is a co-substrate. get inversion at oxygen (R-O-R’) group and the oxygen on the product glucoronide is from the original metabolite/drug.

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13
Q

SULTs

A

substrate is phenolic drugs/metabolites. co-factor is PAPS which is converted to PAP and recycled back to PAPS.
add a -SO3H group onto phenol but at physiological pH the hydrogen is removed forming highly polar compounds.

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14
Q

Glutathione conjugation to mercapturic acid

A

Glutathione (GSH) is the substrate and reacts with drug/metabolite directly or via GSTs. Attack electrophilic sites on drug/metabolite.
Usually seen when deactivating reactive groups like epoxides, quinones and halides.
Rarely excreted as glutathione conjugates but instead are converted to mercapturic acid conjugates and then excreted.

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15
Q

APAP metabolism

A

glucuronidation and SULTs are major elimination pathways. Also have CYP2E1 that converts APAP to NAPQI which is a highly reactive electrophile. GSH reacts with NAPQI to form mercapturine and excretion. But if GSH levels are saturated NAPQI will start reacting with proteins and cell death will occur. Alcohol induces CYP2E1 that is why you never take APAP and alcohol.

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16
Q

P450 Structure

A

ER membrane bound. heme prosthetic group is the catalytic center of the enzyme. active site of the enzyme is located in a hydrophobic region in interior (makes sense because most drugs are hydrophobic).

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17
Q

Monooxygenation

A

P450 catalyzed reaction where molecular oxygen is bound by heme group and one oxygen eventually is incorporated into the substrate and the other is converted to water.

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18
Q

Metabolic Specificity of P450s

A

defines which molecules are accepted as substrates by a particular P450 (substrate selectivity) and what site or sites on a particular molecule are oxidized by a particular P450 (product profile)

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19
Q

P450 Reactions (5 reactions)

A

Oxidation of sp3 carbon-hydrogen bonds, O-dealkylation, N-dealkylation, oxidation of sp2 carbon-carbon bonds, oxidtion of double bonds in aromatic systems to make arene oxides and phenols.

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20
Q

Oxidation of sp3 carbon hydrogen bonds

A

formation of alcohol.
omega -1 carbon more susceptible to hydroxylation vs. the omega carbon.

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21
Q

O-dealkylation

A

cleave alkyl ethers to form alcohols
hemiacetal intermediate
often alcohol products are a substrate for GTs.

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22
Q

N-dealkylation

A

cleave alkyl groups from alkylamines to make amine and aldehyde/ketone fragment.
carbinolamine intermediate

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23
Q

Oxidation of sp2 carbon-carbon bonds

A

isolated carbon-carbon bond oxidation to give epoxides.
epoxides are unstable, electrophilic and sometimes toxic.
eventually reacts with water to give diol through enzymes called epoxide hydrolases.

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24
Q

Oxidation of double bonds in aromatic systems to make phenols

A

intermediate is an epoxide in an aromatic ring and is called an arene oxide.
arene oxide rapidly rearranged by NIH shift to phenol.

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25
NIH shift
mechanism used in oxidation of double bond in an aromatic system to generate an arene oxide and then a phenol
26
Advantages of having multiple enzymes involved in a drugs metabolism.
Even if an individual in the population can't metabolize a drug with a certain CYP if the drug is metabolized by multiple CYP enzyme then metabolism still occurs and drug does not remain in body.
27
Complications of drug therapy due to variability in metabolism
- phenotypic variability (variable levels of enzyme expression in the population at large) - genotypic variability (polymorphic forms of P450 enzymes) - enzyme induction (drugs that can increase amounts of P450 enzymes) - enzyme inhibition (drugs that can inhibit P450 enzymes)
28
Desirable properties of a drug from the perspective of metabolism
- don't cause DDIs - metabolic clearance is constant in the population - metabolites are benign - Dosing is simple in the population
29
Factors that can affect the levels/activity of P450
1. baseline interindividual variability in the constitutive levels of P450 enzymes 2. genetic polymorphisms. especially important in CYP2D6 3. presence of drugs or dietary constituents that induce levels of P450 enzymes 4. presence of drugs or dietary constituents that inhibit activity of P450 enzymes.
30
Genetic Polymorphisms in the CYP2D6 enzyme
- EM is extensive metabolizer. has two wild-type copies. - IM is intermediate metabolizer. has one copy of the wild type and one copy of the null \*4 gene. impaired metabolism is seen but is not a problem and practically speaking can be combined with EM - PM are poor metabolizers and homozygous for \*4 null gene. do not express any functional enzyme. 7-10% caucasian population. - ERM's are extremely rapid metabolizers and have multiple copies of the wild type. they have high levels of active enzyme and are relatively rare.
31
Object Drug
the drug whose metabolism has been altered by the Interactant drug.
32
Interactant Drug
the drug that is causing a change in the activity or amount of enzymes that control the metabolic clearance of the object drug
33
Smoking CYP and example
smoking is an inducer of CYP1A2. object drugs are theophylline, clozapine and caffeine. dosing for these object drugs has to increase in smokers to receive benefit.
34
Rifampin and Midazolam CYP3A4 inducing effects
given an oral dose you see a larger inducing effect than if the dose was given IV because enzyme levels are doubled at both enterocytes and liver thus quadrupling the metabolism in an oral dose. rifampin is inducer. the effect of rifampin on bioavailability is very large due to first-pass effects when given IV vs oral and with more clearance due to induction.
35
Extent of Inhibition
The extent of inhibition will be a function of the inhibitor levels in the blood so inhibition of object drug metabolic clearance depends on the dose and blood levels of the interactant drug.
36
Reversible Inhibition
the inhibitor competes for enzyme with the object drug. Ki is the concentration of inhibitor needed to reduce free drug enzyme by a factor of 2 (50% lower). lower Ki is a more potent inhibitor. each enzyme inhibitor pair has a characteristic and constant Ki (means we can apply the Ki from one inhibitor and CYP pair to all object drugs)/
37
Irreversible Inhibition
Also called mechanism based enzyme inactivation (MBI). binding of enzyme with the inhibitor produces an inactive enzyme that is permanent. time dependent process. example is troleandomycin, diltiazem. Metabolic Intermediate complexes (MICs) are the reactive intermediates that bind directly to the heme iron in P450
38
Principle Concept in Inhibition
Effect of an interactant drug will be observed on all object drugs metabolized by that enzyme.
39
Intentional DDI example
Ritonavir and Saquinavir (used for HIV). sub-therapeutic doses of ritonavir are sufficient to inhibit P450 enzymes enough to increase the AUC of Saquinavir with the same dosage.
40
Prodrug
inactive drugs that undergo a chemical or biochemical conversion to the active drug.
41
Advantages of prodrugs
allows us to circumvent problems delivering a new drug moiety to the site of action such as poor bioavailability and toxicity to the parent drug. And to improve the efficacy of older drugs, usually to improve absorption.
42
Disadvantages of prodrugs
enzyme may be subject to polymorphisms where PMs are unable to get a therapeutic benefit, or polytherapy may lead to inhibition of the "activating" enzyme by other drugs
43
Enzymes that catalyze bioconversion reactions
carboxylesterases, phoshoesterases and P450s
44
Acetaminophen CYP
CYP2E1. APAP was an example of how CYP conversion can be a negative thing. CYP2E1 converts APAP into NAPQI which is reactive with proteins in the cell. Glutathione is used to deactive NAPQI.
45
Caffeine CYP and example
CYP1A2 accounts for 90% clearance of caffeine. example we looked at was inducing effect of smoking on caffeine consumption and answered the question about why so many people who quit smoking can't sleep. Answer they had to drink more caffeine while smoking to get same effect.
46
aflatoxin CYP and example
CYP3A4 and CYP1A2. procarcinogen found in fungi or peanuts and corn. example was to show that mutlitple enzymes and multiple metabolites are a positive thing and to understand product and substrate specificity. There are three sites of CYP action. 2 produce hydroxylation/O-dealkylation but the third produces an epoxide that needs to be deactivated.
47
TCAs CYPs and explain the example we used.
CYP2D6. The example in class we used was to look at TCA (nortryptyline) dosing in different CYP2D6 populations (EM vs PM) to determine how much of the dose was metabolized by the CYP enzyme.
48
Codeine CYPs and example used in class.
CYP2D6. conversion of codeine to its metabolite morphine gives analgesic effects. Only 10% of the codeine dose is converted by CYP2D6. if an individual is PM for CYP2D6 they may not receive benefits for analgesia. Codeine itself is a cough suppressant.
49
Tamoxifen CYP
CYP2D6. anticancer. afimoxifene is metabolite and is equal or more reactive than the parent drug. example of personalized medicine. if knew the profile of patient for CYP2D6 could better dose the drug.
50
Plavix CYP and example
CYP2C19. metabolite is active and Plavix is inactive. example was that there is a black box warning that poor metabolizers are at risk of clots after surgery. null CYP is \*2 which is inactive. 15-20% of asians are PM.
51
Warfarin CYP and example
CYP2C9. warfarin 85% of clearance due to CYP2C9. Warfarin has a very low therapuetic index and is dosed to effect (INR measure of how fast it takes blood to clot) In PM dose must be reduced significantly to avoid toxic affects of warfarin. Also, looked at effect of rifampin on warfarin plasma concentrations and prothrombin activity. plasma dropped after rifampin was added, as did the prothrombin time.
52
alfentanil CYP and example. (figure)
synthetic opioid parenteral use. CYP3A4. compared plasma concentration time curves for alfentanil as a control then added rifampicin (antibacterial inducer of CYP3A4) and separately Troleandomycin (erythromicin inhibitor of CYP3A4). Compared clearance and half life in the three groups.
53
Rifampin CYPs
induces CYP3A4, CYP2C9, CYP2C19. usually always used as the inducer for the examples in class.
54
troleandomycin and other erythromycin analogs CYP
inhibit CYP3A4. used in an example with alfentanil and midazolam to show effects of inhibiting CYP3A4. longer half life and lower clearance
55
midazolam CYP and example.
CYP3A4 responsible for 90% of clearance. used in an example with troleandomycin and rifampin to compare induction and inhibition of CYP3A4 on midazolam levels. Also compared to the effects on afentanil: see same pattern of effects on half life and clearance. importance: if a group of object drugs are metabolized significantly by a given enzyme then the effect of a given interactant drug on clearance should be seen for all of those object drugs.
56
theophylline CYP and example
CYP1A2. used to treat asthma. example we used was with induction by cigarette smoking. dose increase of 60% necessary in smokers vs the normal population. Therefore about 60% of the clearance of theophylline is due to CYP1A2
57
Clozapine CYP and examples
CYP1A2. antipsychotic. example in class was with cigarette smoking as an induction effect. After quitting smoking doses had to be decreased 2-3 fold which means most of the metabolism of clozapine is due to CYP1A2.
58
carbamazepine CYP and example
inducing CYP3A4. used for epilepsy. example in class: study done found that low dose OC performs poorly when given with carbamazepine.
59
birth control CYP and example.
CYP3A4. example in class was a study done looking at the effectiveness of low-dose OC while also taking carbamazepine which is an inducer of CYP3A4. results were that OC was not effective.
60
fluvoxamine CYP and example
inhibits CYP1A2. used as an example to show that the extent of inhibition is dependent on the inhibitor levels in the blood.
61
tolbutamide CYP and example
CYP2C9. example was with the inhibitor sulaphenazole. See higher AUC and lower Cl after using inhibitor. New steady state takes awhile to reach for tolbutamide implying that it has a long half-life.
62
sulfaphenazole CYP and example
CYP2C9 inhibitor. example with tolbutamide and effects on AUC and clearance. We then said that any drug cleared by CYP2C9 will experience an interaction with sulfaphenazole.
63
terfenadine CYP and example
CYP3A4. Example: gave parent drug and noticed that levels of terfenadine in the blood were very low compared to the level of the metabolites. CYP3A4 converts \>99% of parent to metabolite on first pass. Allegra is the metabolite (now called fexofenadine) and antihistamine effects due mostly to this metabolite. And rare cardiotoxic effects were due to the parent drug. People who experienced these effects were taking other compounds that inhibited CYP3A4.
64
Rotinavir CYP and example
CYP3A4 inhibitor (time dependent loss, irreversible MBI). HIV. now used as a boosting agent to increase saquinavir AUC levels. Give a sub-therapeutic dose. But also reacts with other drugs patient may be taking that have negative effects like flonase (example in class).
65
flonase CYP and example
CYP3A4. compared AUC for flonase control and flonase administered with ritonavir (inhibitor). 350-fold increase in AUC with ritonavir.
66
Induction of P450
induction of enzyme levels normally takes a few days to reach full effect. similarly de-induction due to removal of an inducing agent also takes days. Adding an inducer will result in subtherapeutic concentrations of the object drug.
67
Debrisoquine (DB) and CYP and example used in class.
DB is converted by CYP2D6 to 4-OH-DB. used as a test drug to determine phenotype of individual. take ratio of parent drug DB to metabolite in urine six hours after dose. EMs will have a small ration and PMs will have a large ratio. DB is good to use because is metabolized solely (or near completely) by CYP2D6
68
Cyclosporine CYP and example
CYP3A4. used as an example to show affect of clearance and AUC when given with phenytoin (CYP3A4 inducer). Clearance increased 100% which means AUC must of decreased 100%
69
phenytoin CYP and example
CYP3A4 inducer (also induces CYP2C9). used as an example to show the effects of AUC and CL when CYP3A4 was induced on cyclosporin.
70
Cimetidine CYP and example
CYP1A2 inhibitor. compared object drug half-life versus no inducer. Also CYP2C9 inhibitor. looked at warfarin and cimetidine used together increasing prothrombin time and plasma warfarin concentrations.
71
Quinolones and example
CYP1A2 inhibitor. compared object drug half life.
72
Tamiflu example
Prodrug. increase in oral absorption and bioavailability. liver esterase.
73
Fluphenazine Esters and example
prodrug. depot injection and can control the rate of entry into blood by making the drug more lipophilic. blood esterases convert drug to active form once the drug gets into blood stream.
74
Enalapril and example
prodrug. inactive ester converted to active acid by carboxylesterases in liver. the metabolit can only be administered IV whereas the prodrug can be taken orally.
75
Valacyclovir and example
Prodrug of acyclovir. increases bioavailability. acyclovir itself is also a prodrug.
76
Capecitabine and example
cancer prodrug. carboxyesterase in liver acts on carbamate. prodrug allows drug to be given orally rather than IV.
77
Ifosfamide and example
prodrug converted by CYP3A4/2B6. anticancer drug.
78
Prasugrel and Plavix example.
both are prodrugs but Plavix is inactivated immediately by an esterase (85%). Whereas, Prasugrel used the esterases to convert to the prodrug, increasing bioavailability. Once to the liver both drugs are converted by CYP2C19 to active drugs.
79
Metabolism-Induced Toxicity
Drugs that undergo metabolism to reactive metabolites that bind to cellular macromolecules and produce a toxicity. Usually have multiple cellular targets.
80
Examples of DILI (drug-induced liver toxicity)
black box warnings: flutamide, halothane.
81
Types of liver injury
Necrosis: cell lysis Apoptosis: phagocytosis of liver cells.
82
Markers of liver injury
rise of enzymes in the blood, liver biopsy (example with APAP and liver)
83
Flutamide and liver failure
anti-androgen for prostrate cancer. nitroaromatic compound. leads to acute hepatitis and acute liver failure. hepatocytes undergo apoptosis. CYP2E1 converts it to a reactive metabolite.
84
Evidence of hepatic injury
In flutamide. elevated serum transaminase levels, hepatic encephalopathy and death. Serum transaminase levels should be measured prior to starting treatment. Risk of hepatitis is increased with daily alchohol intake.
85
Signs and symptoms of liver dysfunction
nausea, vomiting, abdominal pain, fatigue, anorexia, flu-like symptoms, hyperbilirubinuria, jaundice, right upper quadrant tenderness.

MEDCHEM 570 (3 decks)

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