Module 4 Metabolism Flashcards
(48 cards)
1
Q
Drug Metabolism Definition
A
- Enzyme mediated alteration of drug structure
- Biotransformation
2
Q
Metabolism Sites
A
- Liver
- Intestine
- Stomach
- Kidney
- Intestinal bacteria
3
Q
Liver Site
A
- Primary metabolism site
4
Q
Intestine Site
A
- Enterocytes on gut lining metabolize
5
Q
Stomach Site
A
- Alcohol metabolism
6
Q
Intestinal Bacteria SIte
A
- Bacterial flora
7
Q
Drug Metabolism Importance
A
- Protection from toxins
- Synthesize endogenous molecules
8
Q
Endogenous Examples
A
- Vit D synthesis
- Bile acid synthesis
- Cholesterol metabolism
- Steroid hormones
- Bilirubin
9
Q
Therapeutic Consequences
A
- Increase water solubility of drugs, promoting excretion
- Inactive drugs
- Increase drug effectiveness
- Activate prodrugs (inactive until metabolized)
- Increase drug toxicity
10
Q
1st Order Kinetics
A
- Directly proportional to free drug concentration
- Constant fraction of drug metabolized per unit time
- Drug concentration lower than metabolic capacity
11
Q
0 Order Kinetics
A
- Plasma drug concentration higher than metabolic capacity
- Constant metabolism over time
- Ethanol
12
Q
First Pass Metabolism
A
- Metabolism prior to entering circulation
- Decrease amount of parent drug in circulation
13
Q
Mechanisms of First Pass
A
- Hepatocytes in lives
- Intestinal enterocytes
- Stomach
- Intestinal bacteria
14
Q
Extraction Ratio
A
- Metabolism amount on first pass through liver
- Determine bioavailability
- High/low ratio characterization
15
Q
High Extraction Ratio
A
- Low oral bioavailability
- High PO dose, low IV dose
- Small changes in hepatic enzyme
- Produce large changes to bioavailability
- Susceptible to drug/drug interactions
16
Q
Low Extraction Ratio
A
- High oral bioavailability
- PO & IV doses similar
- Hepatic enzyme changes no effect on bioavailability
- Not susceptible to drug/drug interactions
- Many passes through liver
17
Q
Metabolism Phase 1
A
- Convert lipophilic drugs to polar molecules (OH/NH2)
- Oxidation, reduction, hydrolysis reactions
- Mediated by cytochrome, esterases, dehydrogenases
- Metabolites formed more/less active or same as parent drug
18
Q
Glucuronidation
A
- Phase 2 metabolism
- Addition of glucuronic acid (UGTs)
- Create metabolite glucuronide
- Excreted in bile/urine
19
Q
Metabolism Phase 2
A
- Increase polarity of lipophilic drugs by conjunction reactions
- Addition of water soluble molecule
- Conjugates sugar, sulfate, amino acids
- Metabolites less active than parent drug
20
Q
Phase 1 Intracellular Site
A
- Localized to smooth endoplasmic reticulum (ER)
21
Q
Phase 2 Intracellular Site
A
- Drug metabolisers on cytosol side of cell
- Glucuronidation exception ER
22
Q
Cytochromes P-450 Drug Metabolizing Enzymes
A
- Phase 1 of metabolizing
- Hepatic enzymes majority
- Oxidize drugs by adding oxygen
- Produce water by product
23
Q
CYP Naming
A
- 12 families
- Sub families
- Isozyme
24
Q
Phase 2 Metabolizing Enzymes
A
- UDP-glucuronosyltransferases
- Sulfotransferases (SULTs)
- Glutathione S Transferases (GSTs)
- N-acetyltransferases (NATs)
- Thiopurine Methyltransferase (TPMT)
25
UDP-Glucuronosyltransferases (UGTs)
- Localized to smooth ER
- Catalyze transfer of glucuronic acid (sugar) to drug
- Polar
- Easily excreted
- 19 enzymes
26
Sulfotransferases (SULTs)
- Cytosolic
- Catalyze transfer of sulfate group to hydroxyl group
- Polar
- Easily excreted
- 11 enzymes
27
Glutathione S Transferases (GSTs)
- Cytosolic or microsomal
- Catalyze transfer of glutathione molecule to drug
- Transfer of glutathione onto a reactive
- Metabolite less toxic
- 20 enzymes
28
N-acetyltransferases (NATs)
- Cytosolic
- Catalyze transfer of acetyl group from acetyl CoA
- Subject to general polymorphisms
- Cause of variability to drug response
- 2 enzymes
29
Thiopurine Methyltransferase (TPMT)
- Cytosolic
- Catalyze transfer of methyl group
- Subject to general polymorphisms
- Effects on drug safety
30
Affecting Factors of Drug Metabolism
- Age
- Drug interactions
- Disease state
- Genetic polymorphisms
31
Age
- Expression & activity changes
- Enzymes develop by age 2
32
Drug Interactions
- Enzyme inducers
- Enzyme inhibitors
33
Enzyme Inducers
- Cell synthesizes enzyme in response to drug/chemical
- Specific CYP isozymes susceptible to induction
- Increases drug metabolism
34
Consequences of Increased Metabolism
- Decreased plasma concentration
- Decreased drug activity (metabolite inactive)
- Increased drug activity (metabolite active)
35
Enzyme Inhibition
- Certain natural compounds inhibit CYPs
- Decreasing drug metabolism
36
Consequences of Decreased Metabolism
- Higher plasma drug concentration
- Increased therapeutic effects of drug
- Increased drug toxicity
37
Disease State
- Role in CYP activity
- Liver, kidney, infection, inflammatory
38
Genetic Polymorphisms
- Genes have single nucleotide polymorphisms (SNP)
- Change of single nucleotide in DNA
- Affect production of drug metabolizing enzyme
39
Phase 1 SNP
- Metabolizes anticoagulant drug warfarin
- Polymorphism of CYP2C9
- Enzyme activity decrease
- Lower dose required
40
CYP2D6 Function
- Metabolizes codeine to morphine
41
CYP2D6 Phenotypes
- Ultra-rapid metabolizer (UM)
- Extensive metabolizer (EM)
- Intermediate metabolizer (IM)
- Poor metabolizer (PM)
42
Extensive Metabolizers (EM)
- Normal enzymatic activity
43
Intermediate Metabolizers (IM)
- Reduced metabolic activity
44
Poor Metabolizers (PM)
- Almost no metabolic activity
45
Ultra-Rapid Metabolizers (UM)
- Increased CYP2D6 activity
- Multiple copies of CYP2D6 gene
46
Phase 2 SNP
- UGT1A1
- Polymorphisms decrease activity
- Glucuronidases anti-cancer compound (irinotecan)
- Bone marrow suppression
47
NAT 2
- Acetylates isoniazid, caffeine & cancer chemicals
- 23 SNP with NAT2 gene
- Rapid/slow acetylators based on genotype
48
Slow Acetylators
- Susceptible to isoniazid toxicity
- Neuropathy/hepatoxicity
- Risk of cancer development
