Nicolic Flashcards
1
Q
Factors that affect metabolism:
Inter-Individual Factors
A
Constant during an organism’s life-time
Animal Species
Genetics = genetic polymorphism
Sex
2
Q
Dexmethazone
Carbamezapine
A
3A4 INDUCER
- Reduce efficacy of 3A4 substrates
- Estradiol (birth control)
- –> pregnancy
- Estradiol (birth control)
3
Q
Celecoxib
Fluvastatin
Sulfamethazole
A
2C9
Substrate
4
Q
Phase 1 Metabolism:
Enzymes
A
CYP450
Epoxide Hydrolase
Glutathione S-Transferase
5
Q
Clozapine
Imipramine
Tacrine
Theophylline
CAFFEINE
A
1A2
Substrate
6
Q
Which p450 enzymes are known to be
Genetically Polymorphic
A
2C19
2D6
- 2D6 is polymorphic but not inducible
7
Q
P450 General Rxn
A
Incorporate 1 atom of OXYGEN into substrate
Monooxygenase
- electron donor is NADPH
- nicotinamide adenine dinucleotide phosphate
8
Q
Oxybutynin
Carbamazepine
A
3A4 Substrates
9
Q
A
10
Q
Riluzole
Tacrine
Mexillitine
Clozapine
A
1A2
Substrate
11
Q
Clopidogrel (prodrug)
+ Omeprazole
A
Clopidogrel (prodrug) = 2C19 Substrate
+
Omeprazole = 2C19 INHIBITOR
= Less active metabolite of clopidogrel
–> Increase risk of heart attacks
12
Q
Tamoxifen (Prodrug)
+
Antidepressants
or BLACK COHOSH
A
Nearly 1/3rd of patients on Tamoxifen are on
Antidepressants = 2D6 Inhibitors
- Antidepressants reduce hot flashes caused by tamoxifen
- Hot flashes is a side effect (meaning Tamoxifen is WORKING)
- –> REDUCES EFFICACY OF TAMOXIFEN
- since Tamoxifen is a prodrug its metabolites are active
13
Q
CYP450
Info / Naming
A
Most important P1 enzyme
Highest concentration in Liver
Found in ER
MW = 45-60k
450nm in absorption spectrum
14
Q
Which isoforms are INDUCIBLE?
A
Almost ALL are inducible to extent
- 2D6 (nitrogen one)*
- has NO MEANINGFUL XENOBIOTIC INDUCER KNOWN*
- BUT inducible in PREGNANCY*
15
Q
Consequences of enzyme INHIBITION
for drug metabolism
A
Begins with the FIRST DOSE of the inhibitor
–> can lead to TOXICITY
Increase serum conc of second drug
16
Q
Beta blockers
Metoprolol
Penbutolol
Propranolol
Timolol
A
2D6 Substrates
17
Q
Phase 1 Reactions
A
Involve small structural change in the drug molecules
Functionalization
-
Oxidation
- Introduces polar groups
- Reductions
- Exposes polar groups
- Hydrolysis
- Modifies group to be more polar
18
Q
Debrisoquiline
Sparteine
A
2D6 Substrates
19
Q
Cyclosporin
A
3A4 Substrates
20
Q
Acetaminophen
Ethanol
A
2E1 Substrates
Ethanol = also an INDUCER, both
21
Q
CYP450 Superfamily
Info
A
- Many subfamilies / isoforms
- only 15 are involved in drug metabolism
- many involved in metabolism of endogenous compounds (bile/steroids)
- Only family 1/2/3 are responsible for metabolism of drugs
22
Q
Phase 1 Metabolism:
Pharmacological Consequenses
A
- Activity is LOST
- termination of pharmacological activity
- Activity remains
- active metabolites
- Activity of metabolism can be weaker or stronger
- Metabolic Activation = Therapeutic
- PRODRUGS
- Metabolic Activation = Toxic
- Toxic metabolites (acetaminophen)
23
Q
Omeprazole
Lansoprazole
Pantoprazole
A
2C19 Substrates
24
Q
Statins
A
3A4 Substrates
25
Naproxen
2C9 & 1A2
Substrate
26
**Cimetidine**
**Protease Inhibitors**
3A4 ***INHIBITORS***
27
**Grapefruit Juice**
*Furanocoumarines*
3A4 ***INHIBITOR***
* Increase BV of 3A4 substrates
* benzodiazepines
* statins
* antihistamines
* CCB's (felodipine)
28
Clomipramine
Cyclophosphamide
**Progestrone**
2C19
Substrate
29
Factors that affect metabolism:
**INTRA**-individual factors
**Variable** during organism's life time
**Enzyme INDUCTION / INHIBITION**
**Age**
**Diseases** (liver specifically)
**Pregnancy / Stress**
**Nutrition** (obesity/dietary supplements)
30
**Calcium Channel Blockers**
**Nifedipine**
3A4 Substrate
31
**P450 Active Site**
**Heme** (iron protoporphyrin IX)
in **hydrophobic pocket**
* Iron in the middle of **4 pyrrole rings**
* 5th ligand is **thiolate anion**
* from cysteine residue of apoprotein
32
**Benzodiazepines**
Alpra**zolam**
Dia**zepam**
Mida**zolam**
3A4 Substrates
33
**Warfarin**
**Tamoxifen**
Tolbutamide
Torsemide
2C9
Substrate
34
**Barbiturates**
**Rifampicin**
**INDUCERS OF:**
**3A4**
**2C19**
**2C9**
35
Ethanol
Isoniazid
2E1 **INDUCERS**
Ethanol is also a Substrate of 2E1
36
**Chronic Alcoholism**
Ethanol **INDUCES 2E1**
--\> Acetaminophen **Liver Toxicity**
* Alcoholism --\> MORE 2E1
* Acetaminophen gets more conversion to bad substrate
* --\>toxicity
37
**St. John's Wort**
| (Hyperforin)
3A4 **INDUCER**
Activates pregnane X receptor, regulates transcription of CYP3A4
* Herb to improve Mood
* Reduces efficacy/BioAvailability of 3A4 substrates
* Cyclosporin (prodrug)
* Antidepressants
* Birth control
* HIV (indinavir drugs)
* Cancer Drugs
* Warfarin
38
Enzyme Induction
*May increase Metabolism of drug*
***--\>*** reduce drug activity
* Effects of induction can be seen within **2 days**
* can takes **more than a week** for new enzymes to be synthesized (max effect)
* = **TOLERANCE**
* **Typically Reversible**
39
Opiates
Fentanyl / Methadone / Alfentanil
3A4 Substrates
40
Diazepam
Amitriptyline
2C19
Substrate
41
**Cigarette Smoke**
**1A2 INDUCER**
* Reduce Fxn of 1A2 substrates
* Theophylline + SMoke
* --\> asthma attack
* CAFFEINE
42
Erythromycin
3A4 Substrates & ***INHIBITOR***
43
Estradiol
Sildenafil
3A4 Substrates
44
7-15% of **Caucasians**
**are genetically *DEFICIENT in....***
*DEFICIENT in **CYP2D6***
Due to genetics
* POOR METABOLIZERS **(PM)** of
* Antidepressants / Antipsychotics
* Beta Blockers
* Narcotics
* DM / Atomoxetine
* **INCREASE Bioavailability of these drugs**
45
Order of Reactivity for
## Footnote
**P450 oxidation**
**Most Stable Radical = Most Reactive**
**Ease of Nonbonded e- abstraction**
* tendency for oxidation follows the stability of the radicals that are formed
* Carbon radical of benzyl carbon iis more stable than radical of aliphatic carbon
46
**Carbamezapine**
**(tegretol)**
**3A4**
Substrate & **INDUCER**
both!
47
Nefazodone
Protease Inhibitors
Tacrolimus
Tolterodone
3A4 Substrates
48
Phase 2 Metabolism:
Functional group masked by addition of conugate
**Conjugation** -\>
(typically polar *INACTIVE* metabolites)
* **Glucuronidation**
* **Conjugation:**
* **Sulfate**
* **Glutathione**
* **Amino Acid**
49
Experimental steps in drug metabolism studies
1. ***Isolation*** (often can be omitted)
1. extrations/ion exchange
2. **Seperations**
1. HPLC / GC
3. **Identification**
1. ****NMR, mass spectrometry
4. **Quantification**
1. Radioactive labeling, GC/HPLC
50
**Disulfram**
2E1 ***INHIBITOR***
51
Flavoprotein NADPH
**-CYP450 REDUCTASE**
**Electron carrier**
Delivers electron _ONE AT A TIME_
* NADPH --\> NADP
* P450 can only handle 1 electron at a time
* = stepwise manner
* P450 reductase carries the other electron
52
**Azole** Antifungals
Clarithro**mycin** / Erythro**mycin**
**Ciprofloxacin**
3A4 ***INHIBITORS***
* ******Cyclosporin + Ketocon**azole** *(inhibitor of 3A4)*
* **Increase Immune Supression
* --\> transplant rejection
53
Antipsychotics
Haloperidol
Perphenazine
Risperidone
Thioridazine
2D6 Substrates
54
**OTC's**
**Dextromethorphan (DM)**
Cimetidine
Chlorphenir**amine**
Diphenahydra**mine**
Bromphenir**amine**
**2D6 *INHIBITORS***
* Prozac + **DM**
* --\> Increase Prozac antidepressant fxn
* --\> CNS DEPRESSION
55
**P450 Reaction Mechanism**
**2 steps**
* **1)** **Oxygen Activation**
* *CARBON MONOXIDE IS POISON FOR THE RXN*
* *blocks binding --\> kills rxn*
* ****2)** Iron oxo complex **Abstracts H atom**
* Oxygen rebound gives oxidized substrate
56
Tricyclic Antidepressants:
Venlafaxine (effexor)
Fluoxetine
Paroxetine
2D6 Substrates
57
**EDG**
Electron Donating Sustituent
**Ortho / Para** directing
**Enhance Oxidation Rate**
- OH
- CH3 (alkyl)
- NR3 (amino)
58
Methadone
Quinidine
Haloperidol
2D6 ***INHIBITORS***
* *Reduce* effectiveness of Codeine
* Codeine is metabolized by 2D6 into morphine
* morphine = active form
* less morphine is metabolized due to less 2D6
59
**EWG**
Electron Withdrawing Group
**Meta Directing**
**Slow/prevent aromatic hydroxylation**
**-X (halogens)**
- NO2 (nitro)
- Carbonyl groups
- NH3+ (ammonium salt)
60
CYP**2D6**
Role in hepatic drug metabolism
* **Only 2% found in liver**
* **But metabolizes 23% of drugs**
* **"PRE-SELECT"** drugs that are substrates for this enzyme
* Basic Nitrogens
* Very specific
61
CYP450 Superfamily
## Footnote
**Family**
\>40% sequence homology
Labeled with **#NUMBERS**
62
Phenytoin
2C19 & 2C9 Substrate
63
**SSRI's**
esp. Paxil / Prozac
2D6
Substrates & ***INHIBITOR***
64
CYP450 Superfamily
## Footnote
**Subfamily**
\>55% sequence homology
Labeled with **Letters**
65
**FMOs**
**"mFMO"**
Flavin Mono-oxygenases
P1 Enzyme
**Oxidize Nucleophilic Atoms**
**N / S / P --\> N-O / S-O / P-O**
Found in _liver / kidney / lung / intestine_
* _DIFFERENT mechanism_ to heterocycle oxidation by CYP450
* But end-product is similar
* More specific to **N- / S- oxidation**
* **_NOT INDUCED BY DRUGS OR POLLUTANTS_**
* __less prone to drug interactions
* Not dependent ton gender/age/smoking history
* intra-individual factors
* Narrower substrate specificity
66
**MAOs**
Monoamine Oxidase
P1 Enzyme
Metabolism of _Endogenous + Exogenous Amines_
**1\* Amine --\> Aldehyde**
**2\* / 3\* Amines --\> Ketone**
* Same product as P450
* but **OXYGEN COMES FROM WATER**
* *not air*
* *oxygen is used for FAD --\> h2o2*
67
**EH**
Epoxide Hydrolase
P1 Enzyme
**Hydrolyses Epoxides --\> DIOLS**
_Microsomal / soluble forms_
_TRANS PRODUCT_
* Double bond + P450 = Epoxide
* Epoxide + **EH** = **Trans Diol**
* *EPOXIDE IS VERY REACTIVE*
* *Can ATTACK NUCLEOPHILES*
* *=TOXICITY*
68
**MAO-A**
P1 Enzyme
Primarily found in the **_CNS_**
also found in _GI Tract / Liver / Placenta_
_outer membrane of mitochondria_
**Serotonin / Epinephrine / Norepinephrine**
(endogenous fxn)
along with MAO-B also, dopamine/tyramine/tryptamine
69
**MAO-B**
P1 enzyme
Primarily found in the **_CNS_**
also found in **_Platelets_**
outer membrane of mitochondria
**Drugs: Phenethylamine, benzylamine**
(EXOogenous fxn)
along with MAO-A also, dopamine/tyramine/tryptamine
70
**Disulfram**
Antabuse
**INHIBITOR of Aldehyde Dehydrogenase**
Aldehyde -/-\> Carboxylic Acid
Used for **Alcoholism**
_Acytlaldehyde product is unpleasant_
Carboxylic acid product is the happy feel
71
**Genetic Polymorphism in**
Aldehyde Dehydrogenase
&
Alcohol Dehydrogenase
**Point Mutation in Aldehyde Dehydrogenase**
Glu787 - Lys487
**Atypical Alcohol Dehydrogenase**
**= FLUSHING SYNDROME**
* FAST Alcohol dehydrogenase
* Alcohol --\> **Aldehyde (negative effects)**
* *SLOW* Aldehyde dehydrogenase
* **Aldehyde** --\> Carboxylic acid (positive0
72
**Quinone Reductase**
NAD(P)H-Quinone Oxidoreductase / DT-diaphorase
P1 Enzyme
**ChemoPREVENTATIVE Enzyme**
**=DETOX enzyme**
**HIGHLY INDUCIBLE by weak electrophiles**
_Brocolli_
Breaks down Quinones --\> UGT substrates (excreted)
* *If quinone goes through P450 Reductase*
* *--\> SUPEROXIDE ANION RADICAL = ROS*
* *Toxic, can cause oxidative stress*
73
**Esterase**
Hydrolytic P1 Reaction
**R-COOR**
**Ester --\> Carboxylic Acid + Alcohol**
**FASTER**
Most succeptible to Hydrolysis
*vs amides / carbamates (amidase)*
**_ASPIRIN_** (prodrug)
Many **prodrugs** are Esters (also improve **taste**)
**_PROCAINE_**
74
**Amidase**
Hydrolytic P1 Reaction
**Amide --\> Carboxylic Acid + Amine**
* SLOWER than esterase*
* less succeptible to hydrolysis*
**_Procainamide_**
*orally active, resistant to hydrolysis (slower)*
75
Order of Susceptibility to **Hydrolysis**
**Ester \> Thioester**
Carbonate \>
**Amide \> Carbamate \>**
Ureide
76
**Which Enzymes are known to be genetically polymorphic?**
**CYP2C19**
**CYP2C9**
**Alcohol Dehydrogenase / Aldehyde Dehydrogenase**
77
**Which RXN does the OXYGEN come from WATER?**
**MAO**
Oxygen comes from water unlike P450 (from the air)
