Lecture 4 Flashcards
Pharmacokinetics: metabolism (45 cards)
1
Q
What is drug metabolism?
A
- enzyme mediated alteration of a drugs structure
- also called biotransformation
2
Q
what are some sites of drug metabolism?
A
- liver: primary site of drug metabolism
- intestine: enterocytes that line the gut are able to metabolize drugs
- stomach: a site for the metabolism of alcohol
- kidney: under appreciated as a metabolic organ
- intestinal bacteria: normal bacterial flora play an important role in drug metabolism
3
Q
Why do we need drug metabolism?
A
- protects us from environmental toxins (exogenous toxins)
- synthesizes essential endogenous molecules
- makes drugs more hydrophilic so they can be excreted from the body
4
Q
Common exogenous toxins that drug metabolism protects us from
A
- wine
- cigarettes
- steak
- coffee
- drugs
- vegetables
5
Q
Common endogenous toxins that drug metabolism protects us from
A
- Vit D synthesis
- bile acid synthesis
- cholesterol metabolism
- steroid hormones
- bilirubin
6
Q
Therapeutic consequences of drug metabolism
A
- increased water solubility of drugs to promote their excretion (lipophilic –> hydrophilic)
- inactivate drugs (active –> inactive)
- increased drug effectiveness
- activate prodrugs (which are inactive until metabolized)
- increase drug toxicity
7
Q
First order kinetics of drug metabolism
A
- occurs when the concentration of drug is much lower than the metabolic capacity of the body
- metabolism is directly proportional to the concentration of free drug
- concentration decreases faster when there are higher drug concentrations
- enzyme concentration > drug concentration
8
Q
Zero order kinetics of drug metabolism
A
- occurs when plasma drug concentration is much higher than the metabolic capacity of the body
- metabolism is constant over time = constant amount of drug is metabolized per unit time
- metabolism is independent of drug concentration
- drug concentration > enzyme concentration
- good ex.= ethanol
9
Q
what is first pass metabolism?
A
- when PO drugs undergo significant metabolism prior to entering the systemic circulation
10
Q
How can first pass metabolism occur?
A
- hepatocytes in the liver
- intestinal enterocytes
- stomach
- intestinal bacteria
11
Q
What is the result of 1st pass metabolism?
A
- decreased amount of parent drug enters the systemic circulation
12
Q
What is the extraction ratio?
A
- drugs are characterized as having high or low ER depending on how much metabolism occurs on the first pass through the liver
13
Q
Characteristics of high ER drugs
A
extensively metabolized on 1st pass through liver
- have low oral bioavailability (1-20%)
- PO doses usually much higher than IV doses
- small changes in hepatic enzyme activity = large changes in bioavailability
- very susceptible to drug-drug interactions
14
Q
Characteristics of low ER drugs
A
barely metabolized on 1st pass
- high oral bioavailability (>80%)
- PO doses similar to IV doses
- small changes in hepatic enzymes have little effect on bioavailability
- not very susceptible to drug-drug interactions
- take many passes through liver via systemic circulation before completely metabolized
15
Q
What is Phase I metabolism?
A
- converts lipophilic drugs to more polar molecules by introducing or unmasking polar functional groups such as (-OH) or (-NH2)
- involves oxidation, reduction, and hydrolysis rxns
- metabolites can be more, less, or equally as active as parent drug
16
Q
What enzymes mediate phase I metabolism and where are they localized?
A
- cytochrome P450, esterases, dehydrogenases
- localized to the smooth endoplasmic reticulum
17
Q
What is Phase II metabolism?
A
- increases the polarity of lipophilic drugs by conjugation rxns (addition of large water soluble molecules)
- metabolites less active than the parent drug (exception: morphine)
- some drugs enter phase II metabolism directly
18
Q
Conjugates of Phase II metabolism?
A
- glucuronic acid (a sugar), sulfate (-SO4), acetate or amino acids (i.e glycine)
19
Q
Where are Phase II metabolizing enzymes localized to?
A
- cytosol of the cell
- exception: glucuronidation (smooth ER)
20
Q
What are cytochrome p450 (CYPS) drug metabolizing enzymes?
A
- are the predominant phase I drug metabolizing enzyme system
- majority of drug metab done by hepatic CYPs
- oxidize drugs by inserting one atom of O2 into the drug molecule producing water as a product
- 12 families of CYPs, 3 do the most ( CYP3A4 does the most)
- malnutrition decreases CYP activity bc they require dietary protein, iron, folic acid, and zinc
21
Q
CYP nomenclature
A
CYP3A4
3: family
A: subfamily
4: isozyme
22
Q
What enzymes mediate phase II metabolism?
A
- UDP-glucuronosyltransferases (UGTs)
- sulfotransferases (SULTs)
- Glutathione S Transferases (GSTs)
- N-acetyltransferases (NATs)
- Thiopurine Methyltransferase (TPMT)
- relatively equally split between the first 4
23
Q
UGTs
A
- localized to smooth ER
- catalyze the transfer of a Glucuronic acid (sugar) to a drug
- becomes more polar and more easily excreted
- 19 different human UGT enzymes
24
Q
SULTs
A
- cytosolic
- transfer sulfate group to a hydroxyl group of drugs
- more polar & easily excreted
- 11 of them
25
GSTs
- cytosolic or microsomal
- transfer of glutathione molecule which is an intracellular anti-oxidant
- this makes reactive (toxic) drugs less otxic
- are over 20
26
NATs
- cytosolic
- transfer acetyl group from acetyl CoA to a drug making it more water soluble
- subject to genetic polymorphisms which is a major cause of variability to drug response
- 2 of them, NAT 1 and NAT 2
27
TPMT
- cytosolic
- transfer of methyl group from S-adenosylmethionine to a drug
- subject to genetic polymorphisms which can have a dramatic effect on drug safety
28
What are some factors that affect drug metabolism?
1. age
2. drug interactions (enzyme inducers/inhibitors)
3. disease state
4. genetic polymorphism
29
How does age affect drug metabolism?
- expression and activity of metabolizing enzymes increases from infancy to adulthood, but decreases as we become elderly
- infants have almost no CYP activity
- by age 2 we have the same amount of CYP activity as adults
30
What is enzyme induction?
a cell synthesizes an enzyme in response to a drug or other chemical
31
How does enzyme induction affect metabolism?
- CYP enzymes susceptible to induction by drugs leading to increase drug metabolism
- also affects drug interactions
32
Consequences of increase drug metabolism due to CYP induction?
- decreased plasma drug concentration
- decreased drug activity (if metabolite is inactive)
- increased drug activity (if metabolite is active)
33
Consequence of decreased drug metabolism due to CYP inhibition?
- higher plasma drug concentration
- increased therapeutic effect of drugs
- increased drug toxicity
34
Disease states that decrease CYP activity?
- liver disease
- kidney disease
- inflammatory disease
- infection
35
What are genetic polymorphisms?
- also known as single nucleotide polymorphisms (SNPs)
- is a change of a single nucleotide (A,T, G, or C) in our DNA which can affect the protein produced
- there are a number of SNPs in drug metabolizing enzymes that cause pronounced differences to the response of drugs
36
What are the phase I SNPs?
CYP2C9
| CYP2D6
37
CYP2C9
- metabolizes warfarin
- polymorphism of this CYP results in decrease enzymatic activity
- patients with this polymorphism require lower dose of warfarin so they dont experience extensive bleeding
38
CYP2D6
- metabolizes codeine to morphine which is more potent
- has many SNPS that result in 4 distinct phenotypes: ultra-rapid metabolizer, extensive metabolizer, intermediate metabolizer, and poor metabolizer
39
Extensive metabolizers
normal enzymatic activity
40
intermediate metabolizers
lowered activity
41
poor metabolizers
almost no activity
42
ultra-rapid metabolizers
- increased CYP2D6 activity
| - may posses multiple copies of the CYP2D6 gene
43
What are the Phase II SNPs?
- UGT1A1
| - NAT2
44
UGT1A1
- polymorphisms = decreases activity
| = patients with then polymorphism at risk of diarrhea and dose limiting bone marrow suppression (potentially fatal)
45
NAT2
- acetylates the drug isoniazid, caffiene, and various cancer causing chemicals
- over 23 different SNPs in this gene
- patients classified as either rapid or slow acetylators base on genotype
- slow acetylators are more susceptible to isoniazid toxicity than rapid ones
- slow at risk for developing certain types of cancer
