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71 Cards in this Set
- Front
- Back
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What is a Prodrug?
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A drug that is inactive as given, then subsequently metabolized into its active form
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What are 4 phase I metabolism reactions?
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-Oxidation
-Reduction -Dealkylation -Hydrolysis |
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What does a Phase I reaction do?
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Introduces or reveals a functional group
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What sort of change does a Phase I reaction result in for a drug?
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Small relative to the whole drug structure
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What is a Phase II metabolism reaction?
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Conjugation of a drug or drug metabolite to an endogenous substrate molecule
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What sort of change does a Phase II metabolism reaction result in? What does it accomplish?
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Bigger changes - makes the drug more polar for elimination
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The 2 processes that prevent continuous drug action are:
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-Elimination/excretion
-Metabolism |
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How do most drug metabolites compare to their parent drugs? (2 ways)
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-More polar
-More hydrophilic |
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Does drug metabolism always inactivate a drug?
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No it may activate a prodrug
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What is a drug that is both inactivated and activated by metabolism?
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Morphine
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What is Drug metabolism often a cause of?
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Drug-drug interactions
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What are 2 ways that drugs can interfere with the metabolism of other drugs?
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1. Acting as competitive substrates for the same drug-metabolizing enzyme
2. Acting as inhibitors of the other drug's metabolizing enzyme |
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Where are the drug metabolizing enzymes located in general?
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In organs at the portals of entry and exit
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What organ has the highest overall content of drug metabolizing enzymes?
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The liver
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What 3 other organs have drug metabolizing enzymes?
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-GI tract
-Kidneys -Lungs/nasal passages (all tissues have some) |
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Where are Phase I enzymes located within cells?
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Smooth ER - microsomal fraction
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Where are Phase II enzymes located within cells?
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Cytosolic
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To what drugs does the First Pass Effect apply?
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Oral drugs
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Where are the enzymes that contribute to the FPE?
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-Intestines
-Liver |
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What is the result of significant metabolism of oral drugs in the intestines and liver?
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It can greatly lower the drug's bioavailability
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What do you have to do for drugs with large FPE to match the efficacy seen with IV administration?
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Increase the dose
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What is Bioavailability?
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Fraction of a dose that reaches systemic circulation
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How would you convert an IV dose to an oral dose for a drug with an F less than 100%?
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Divide IV dose / F
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What are 2 reasons for low F?
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-Poor absorption
-Large first pass effect |
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What are the 2 major types of Phase I enzymes?
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-Cytochrome P450s (CYPs)
-Flavin-containing monooxygenases (FMOs) |
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What are the 5 requirements for the P450 catalytic cycle?
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-Cytochrome 450
-P450 reductase -NADPH -O2 -Drug |
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Where are Cytochrome P450 and the P450 reductase anchored?
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To the cytosolic face of the sER
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What is the molecular ratio of isoforms of P450 reductase to cytochrome P450s?
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1:10-20
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What is the reaction type catalyzed by Cyto P450s called?
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A monooxygenase type reaction
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In the example CYP2B10:
-What is CYP -What is 2 (how much identity) -What is B (how much identity) -What is 10 |
CYP = root symbol for cytochrome P450
2 = Gene family >40% identity B = Subfamily >55% identity 10 = isoform |
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How many Cyp families are there? What are the major ones involved in drug metabolism?
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18 exist
CYP1, CYP2, and CYP3 are involved in drug metabolism |
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How many human CYP genes are involved in drug metabolism?
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15
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How do the CYP genes between individuals compare?
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There is significant inter-individual variation
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What is the implication of significant inter-individual variation among CYP genes?
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Significant variability in response to drugs in different individuals!
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What does % identity refer to when we say there is 40% identity between families, and 50% identity between subfamilies?
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% amino acid sequence identity
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What is the Substrate specificity of Cyto P450s like in general?
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Broad - each isoform can have several to hundreds of drug substrates
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Which 3 CYP isoforms handle 90% of metabolizable drugs? What % is handled by each?
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CYP3A - 50%
CYP2D6 - 25% CYP2C9 - 15% |
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Does the % contribution of drug handling by CYPs correlate with the relative CYP isoform content?
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no
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What is the other Phase I enzyme to know?
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FMO - flavin-containing monooxygenase
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What are substrates for FMO reactions?
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Soft nucleophiles
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How do FMOs bind their substrates?
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Through exclusion of nonsubstrates; their active site is very reactive, so when it sees a soft Nu: it binds it
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What are the 4 required components for an FMO reaction?
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-Drug substrate
-O2 -NADPH -FMO enzyme |
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How does the substrate profile for an FMO isoform compare to that of a Cyto P450?
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Much broader
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What are the products of both Cyto P450 and FMO reactions (Phase II metabolism reactions)?
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-More polar
-More ydrophilic -Less toxic |
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What are the major types of reactions catalyzed by Cyto P450s?
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-Hydrolysis
-Oxidation -Reduction -Dealkylation |
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Where are Phase I enzymes located within cells?
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Smooth ER - microsomal fraction
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Where are Phase II enzymes located within cells?
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Cytosolic
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To what drugs does the First Pass Effect apply?
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Oral drugs
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Where are the enzymes that contribute to the FPE?
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-Intestines
-Liver |
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What is the result of significant metabolism of oral drugs in the intestines and liver?
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It can greatly lower the drug's bioavailability
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What do you have to do for drugs with large FPE to match the efficacy seen with IV administration?
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Increase the dose
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What is Bioavailability?
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Fraction of a dose that reaches systemic circulation
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How would you convert an IV dose to an oral dose for a drug with an F less than 100%?
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Divide IV dose / F
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What are 2 reasons for low F?
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-Poor absorption
-Large first pass effect |
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What are the 2 major types of Phase I enzymes?
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-Cytochrome P450s (CYPs)
-Flavin-containing monooxygenases (FMOs) |
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What are the 5 requirements for the P450 catalytic cycle?
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-Cytochrome 450
-P450 reductase -NADPH -O2 -Drug |
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Where are Cytochrome P450 and the P450 reductase anchored?
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To the cytosolic face of the sER
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What is the molecular ratio of isoforms of P450 reductase to cytochrome P450s?
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1:10-20
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What is the reaction type catalyzed by Cyto P450s called?
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A monooxygenase type reaction
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In the example CYP2B10:
-What is CYP -What is 2 (how much identity) -What is B (how much identity) -What is 10 |
CYP = root symbol for cytochrome P450
2 = Gene family >40% identity B = Subfamily >55% identity 10 = isoform |
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What are the top 4 isoforms that contribute to 95% of drug metabolism?
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-CYP2A - 50%
-CYP2D6 - 25% -CYP2C9 - 15% -CYP1A2 - 5% |
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Does the % contribution of a P450 correlate with its relative CYP isoform content?
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no not necessarily
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How does the substrate specificity of P450s compare to FMOs?
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Both are broad, but FMOs are even more broad tham P450
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What are FMO's? How many isoforms?
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-Flavin containin Monooxygenases
-5 isoforms |
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What is the most predominant isoform and where is it located?
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FMO-3 - 2-3% of LIVER protein
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What are the substrates of FMOs?
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Soft nucleophiles
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How do FMOs bind their substrates?
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By exclusion of nonsubstrates
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What are the products of both FMO and P450 metabolism reactions like in general?
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-More polar
-More hydrophilic -Less toxic and easier to excrete |
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What are the requirements of the FMO catalytic cycle?
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-FMO enzyme
-Drug substrate -NADPH -O2 |
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What are the primary types of monooxygenation reactions that FMOs catalyze?
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-N-oxidation
-S-oxidation |
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And what are the main types of reactions that P450s catalyze?
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-Hydrolysis
-Oxidation -Reduction -Dealkylation |
