Drug Metabolism Flashcards
(55 cards)
1
Q
Importance of Drug Metabolism:
A
- Termination of drug action
- Drug activation
- Drug-drug interactions
2
Q
Termination of drug action:
A
- For many drugs, the metabolites are more easily excreted from the body
- Metabolites are most often more polar and hydrophilic
- For many drugs, metabolism inactivates the drug
Active drug ⇒ inactive metabolite
3
Q
Drug activation:
A
- Some drugs (prodrugs) are converted to their active form by metabolic enzymes
Prodrug (inactive) ⇒ active drug
4
Q
Drug-drug interactions:
A
- Many result from drug metabolism issues
5
Q
What are some drugs that were withdrawn because of drug-drug interactions due to drug metabolism?
A
- terfenadine
- mibefradil
- astemizole
- cisapride
6
Q
Phase I metabolism:
A
-
Oxidation, reduction, dealkylation, or hydrolysis reactions
- often introduce or reveal a functional group
7
Q
Phase II metabolism:
A
Conjugation of the drug or drug metabolite to an endogenous substrate molecule
8
Q
How are drugs localized in the body?
A
- Organ distribution
- Subcellular distribution
9
Q
Organ DIstribution:
A
- Liver has the highest content overall of drug metabolizing enzymes
- Other organs with significant content
- gastrointestinal tract
- kidneys
- lungs
- All tissues have some drug metabolizing enzymes
- Distribution varies significantly for specific enzymes
10
Q
Subcellular distribution:
A
- Phase I enzymes: usually smooth ER (microsomal fraction)
- Phase II enzymes: most are cytosolic
11
Q
What is the first-pass effect?
A
- Applies to orally administered drugs
- Following absorption from the GI tract, the portal venous system transports them to the liver
- Significant metabolism can occur prior to reaching the general circulation
- Drug metabolizing enzymes in the liver and/or intestine contribute to the first-pass effect
- Can greatly lower the oral bioavailability of a given drug
12
Q
_______________ are hemeproteins that are major catalysts of _________ biotransformation reactions.
A
- Cytochrome P450s
- Phase I
13
Q
Drugs with a _____________ need higher oral doses to match the effects or efficacy seen with IV administration
A
large first pass effect
14
Q
What are two reasons for a low F (bioavailability)?
A
- Poor absorption
- Large first-pass effect
15
Q
Name some drugs with a large first-pass effect:
A
Drug (F)
- morphine (0.17 – 0.33)
- meperidine (0.52)
- aspirin (0.68)
- propranolol (0.26)
- labetalol (0.18 – 0.25)
- metoprolol (0.38 – 0.50)
- diltiazem (0.44)
- verapamil (0.22)
- nortriptyline (0.51)
16
Q
Example: First-pass effect and oral dosing of morphine
If:
- first-pass effect results in an oral F=0.33
- an IV dose of 10 mg effectively relieves pain
A
Then:
- an oral dose of 30 mg would be needed for same degree of pain relief
- if the oral F=0.17, then an oral dose of 60 mg would be needed
- Essentially, a patient will need 3-6x as much morphine than the IV dose
17
Q
P450 Catalytic Cycle:
A
- Required components:
- cytochrome P450
- P450 reductase (flavoprotein)
- NADPH
- O2
- drug (substrate)
- Monooxygenase-type reactions:
- S + O2 + 2e– + 2H+ ⇒ SO + H2O
- where S = substrate (drug)
18
Q
Subcellular localization:
A
- anchored to the cytoplasmic face of the smooth ER
-
one isoform of P450 reductase, but many cytochrome P450 isoforms
- approx. 10–20 P450 molecules per P450 reductase
19
Q
Human P450s:
A
- 18 families
- (CYP1, CYP2, CYP3)
- 57 human P450 genes
- (15 families largely involved)
- Significant inter-individual variation
- drug metabolism
20
Q
How are drug metabolized by human P450s:
A
- Broad substrate specificity
- each isoform can have several to hundreds of drug substrates
- Cytochrome P450 isoform contribution to human drug metabolism:
% of drugs handled by major isoforms:
- CYP3A: 50%
- CYP2D6: 25%
- CYP2C9:15%
- ≤5% each: CYP1A2, CYP2E1, CYP2A6, CYP2C19
- ***DOES NOT equate to the amount of substrates each P450 can handle***
21
Q
Other Phase I Enzymes
Flavin-containing monooxygenase (FMO):
A
- Flavoprotein localized in smooth ER
- Catalyze monooxygenation reactions, primarily of soft nucleophiles:
- N, S, P & Se moeities
- Cannot handle C (job of the P450s)
- S + O2 + 2e– + 2H+ —> SO + H2O
- Primarily N-oxidation and S-oxidation reactions
- Hundreds of potential substrates:
- some are P450 substrates, others are unique to FMOs
- products are more polar and less toxic/active
22
Q
Required components for FMOs:
A
- FMO
- NADPH
- O2
- drug (substrate)
23
Q
FMO isoforms:
A
5 isoforms (FMO1-FMO5):
- FMO3
- Liver, brain, kidney
- 2–3% of hepatic protein (no other protein is this abundant)
- FMO1
- Kidney, intestine
- FMO2
- Lung (26% African-
Americans) - Non-functional in
Caucasians
- Lung (26% African-
- FMO4
- Kidney, brain
- FMO5
- Liver, kidney
24
Q
Examples of drug substrates
for FMO:
A
- nicotine
- cimetidine
- ranitidine
- spironolactone
- imipramine
- clozapine
- olanzapine
25
Dehydrogenases & Hydrolases:
Dehydrogenases
1. Alcohol dehydrogenase (ADH)
2. Aldehyde dehydrogenase (ALDH)
Hydrolases
1. Epoxide hydrolase (EPHX)
2. Carboxyl esterases
* acetylcholine, procaine, cocaine, aspirin
3. Amidases
* lidocaine, peptide drugs
26
Phase II Drug Metabolizing Enzymes:
**Conjugative Reactions**
* conjugation of an **endogenous chemical group** to the drug
* other examples:
1. methylation
2. glutathione conjugation
3. glucoside conjugation
4. amino acid conjugation
27
What are the possible orders of phase I and phase II enzymes? What does this cooperativity depend on?
* depends on drug, its functional groups, and available enzymes:
1. drug → phase I → excretion
2. drug → phase I → phase II → excretion
3. drug → phase II → excretion
4. drug → phase II → phase I → excretion
28
Comparison of major classes of Phase II reactions:
**Glucuronidation**
* **High energy intermediate:**
* UDP-glucuronic acid
* **Functional groups needed on drug:**
* -OH, -COOH, -NH2, -NR2, -SH
* **Responsible Enzyme(s):**
* UDPglucuronosyl
transferases (UGT)
* **Enzyme localization:**
* endoplasmic reticulum (lumenal face)
29
Comparison of major classes of Phase II reactions:
**Acetylation**
* **High energy intermediate:**
* acetyl-CoA
* **Functional groups needed on drug:**
* -OH, -NH2
* **Responsible Enzyme(s):**
* N-acetyltransferases (NAT)
* **Enzyme localization:**
* cytosolic
30
Comparison of major classes of Phase II reactions:
**Sulfation**
* **High energy intermediate:**
* Adenosine-3'- phosphate- 5'-phosphosulfate (PAPS)
* **Functional groups needed on drug:**
* -OH, -NH2
* **Responsible Enzyme(s):**
* sulfotransferases (SULT)
* **Enzyme localization:**
* cytosolic
31
Comparison of major classes of Phase II reactions:
**Glutathione conjugation**
* **High energy intermediate:**
* drug itself: arene oxides, epoxides, etc.
* **Functional groups needed on drug:**
* aryl halide, arene oxide, epoxide, carbonium ion
* **Responsible Enzyme(s):**
* glutathione S-transferases (GST)
* **Enzyme localization:**
* cytosolic, some endoplasmic reticulum
32
What is the net effect of most phase II reactions?
* Metabolites are usually:
* **more polar** (easier to excrete)
* **inactive or less toxic**
**Exceptions:** acetyltransferases and methyltransferases
33
% of drugs handled by phase II enzymes:
UGTs \> STs \> NATs, GSTs \> TPMT
34
What are some other properties of phase II enzymes?
* Some are **inducible**
* Most have **many substrates**
* Vmax limited by **conventional enzyme kinetics and conjugant supply**
* drug + conjugant → drug-conjugant complex
35
Conjugation capacity & Abundance raw materials for cojugation:
**Glucoronidation**
* Conjugation Capacity Abundance of Raw
* High
* Materials for Conjugation
* High
36
Conjugation capacity & Abundance raw materials for cojugation:
Acetylation
* Conjugation Capacity Abundance of Raw
* Variable
* Materials for Conjugation
* Variable
37
Conjugation capacity & Abundance raw materials for cojugation:
Sulfation
* Conjugation Capacity Abundance of Raw
* Low
* Materials for Conjugation
* Low
38
Conjugation capacity & Abundance raw materials for cojugation:
Glutathione conjugation
* Conjugation Capacity Abundance of Raw
* Low\*
* Materials for Conjugation
* Low\*
39
Why is the **conjugation capacity and abundance** of **GSH low** in humans if the **initial amount of GSH high**?
It is not rapidly replenished
40
What is enzyme induction?
**Exposure to some drugs and environmental chemicals can markedly upregulate enzyme amount and/or activity**
* usually **transcriptional increases:**
1. sometimes translational or protein stabilization
2. more enzyme = faster metabolism
* **most cytochrome P450s** (several isoforms) **are inducible**
1. CYP2D6 not as inducible as others
* **some phase II enzymes** (e.g. UGTs, GSTs) **are inducible**
1. induced by environmental chemicals and some drugs
* **changes the overall proportion of drug-metabolizing enzymes**
41
Which P450 does ethanol induce?
CYP2E1
42
Which P450 does tobacco smoke induce?
CYP1A
43
What are the consequences of induction?
**Can increase or decrease drug effects**
* **Broad substrate specificity** of many of these enzymes: a **single inducer will simultaneously upregulate the ability to metabolize several drugs**
* will **decrease effectiveness** of drugs whose **metabolites are inactive**
* will **increase the effects/toxicity for drugs that are activated** by the induced enzyme
* **Increase metabolism dramatically**
* Inducers are **not quantitatively equal**
44
How long does induction take?
If transcriptional,
* Maximal effects are seen in **1 – 2 days**
45
Is it possible for an inducer to be a substrate?
Inducers **may or may not** be substrates
46
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ may inhibit the metabolism of several drugs.
Drug or environmental chemical
47
Potential types of inhibition:
* **Competitive**
* competitive substrates are a **major cause of drug-drug interactions**
* quinidine (CYP2D6)
* furafylline (CYP1A2)
* Many others
* **Bind CYP heme – disrupts catalytic activity** (non-competitive)
* cimetidine
* ketoconazole, itraconazole
* erythromycin
* others
* **Suicide inhibitors** (irreverisble—non-competitive)
* ethinyl estradiol
* levonorgestrol
* secobarbital
48
How long does inhibition take?
Immediate
49
Extent of inhibition:
* Highly variable:
* Depends on **enzyme and inhibitor**
* Small effects ⇒ very large effects
* Several inhibitors of CYP2D6 can **reduce activity to near zero:**
* amiodarone, bupropion, chloroquine, quinidine
* diphenhydramine, fluoxetine, haloperidol, paroxetine
* propoxyphene, terbinafine
50
How does grapefruit juice interact with drugs?
Grapefruit juice increases drug absorption
* **Furanocoumarin** is the responsible ingredient that **inhibits intestinal CYP3A**
* **Increasing the net amount of drug** that reaches the general circulation
51
How are FMOs affected by induction & inhibition?
* **Not significantly induced** by clinically used drugs
* **Not significantly inhibited** by clinically used drugs
* **less susceptible to competitive substrate inhibition** than are P450s
* **Less potential for metabolic drug-drug interactions**
52
What are some other factors that influence drug
metabolism activity?
* **Age**
* Old and young
* efficacy and/or toxicity
* **Genetics**
* **Disease States**
* Hepatic diseases
* Some cancers
* Infections
* cytokines decrease expression of some P450s
* **Gender**
53
Explain how gender is significant in regards to drug metabolism?
* **Clear differences** in sex hormone metabolism
* More recent findings:
* Women require half the dose of zolpidem (Ambien®)
* While **CYP3A expression is overall similar** between men and women, the **clearance in women is actually slower**
* **6–7% of drugs have \>40% pharmacokinetic differences** between men and women
54
What is the most common cause of acute hepatic failure?
Acetaminophen overdose
55
What factors contribute to acetaminophen hepatotoxicity?
Interplay of:
* multiple phase II reactions
* phase I reaction
* CYP2E1 induction
