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53 Cards in this Set
- Front
- Back
What is a phase I reaction?
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Convert a parent drug to a more polar metabolite by introducing or unmasking a functional group (-OH, -NH2, -SH)
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What is the principle organ of drug metabolism?
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the liver
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What vesicles are responsible for oxidative drug metabolism?
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smooth microsomes
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What are the classes of enzymes in smooth microsomes?
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mixed function oxidases or monooxygenases
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What 4 substances do microsomal drug oxidations require?
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P450, P450 reductase, NADPH, and molecular oxygen
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What is the flavoprotein in the microsomal drug oxidation?
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NADPH-cytochrome P450 reductase
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What does one mole of NADPH-cytochrome P450 reductase contain?
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1 mol each of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD)
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What is the hemoprotein in the microsomal drug oxidation?
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cytochrome P450
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What is the rate limiting step in hepatic drug oxidations?
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P450 heme reduction
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Which phase is faster?
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Phase II
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What are the 4 steps in cytochrome P450 cycle oxidation?
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1. oxidized P450 combines with drug, 2. NADPH donates electron to flavoprotein P450 reductase that oxidizes the P450-drug complex, 3. another electron NADPH reduces molecular oxygen and adds it to the P450-drug complex, 4. the complex transfers the oxygen to the drug substrate
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What P450 isoformis responsible for over 50% of the drug metabolism by the liver?
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CYP3A4
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What does it mean to induce P450 expression?
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to enhance its rate of synthesis or reduce its rate of degradation
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What drugs incude CYP1A enzymes?
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benzo(a)pyrene and polycyclic aromatic hydrocarbons
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What receptor uses lipid-lowering drugs as ligands?
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peroxisome proliferator receptor alpha (PPARalpha)
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PPARalpha mediates the induction of what enzyme?
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CYP4A
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What is CYP4A enzymes responsible for?
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metabolism of fatty acids (arachidonic acid)
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PXR, CAR, and PPARalpha for heterodimers with what other nuclear receptor?
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retinoid X-receptor (RXR)
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What is substrate stabilization in reference to P450 enzyme inducing?
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substrate stabilization
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What are suicide inducers?
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inactivators that attack the heme or the protein moiety
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What occurs in phase II reactions?
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parent drugs or phase I substrates undergo coupling or conjugation reactions with an endogenous substance to yield drug conjugates
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In glucuronidation, what is the transferase, where is it located, and what is the endogenous reactant?
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UDP glucuronosyltransferase (UGT) in the mitochondria, uses UDP glucuronic acid
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In acetylation, what is the transferase, where is it located, and what is the endogenous reactant?
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N-acetyltransferase (NATs) in the cytosol, uses acetyl-CoA
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In Glutathione conjugation, what is the transferase, where is it located, and what is the endogenous reactant?
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GSH-S-transferase (GST) in the cytosol and microsomes, uses glutathione (GSH)
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In Glycine conjugation, what is the transferase, where is it located, and what is the endogenous reactant?
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Acyl-CoA glycinetransferase in the mitochondria, uses glycine
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In sulfation, what is the transferase, where is it located, and what is the endogenous reactant?
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Sulfotransferase (SULT) in the cytosol, uses phosphoadenosyl phosphosulfate (PAPs)
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In methylation, what is the transferase, where is it located, and what is the endogenous reactant?
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transmethylases (MT) in the cytosol, uses S-Adenosylmethionine (SAMe)
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In water conjugation, what is the transferase, where is it located, and what is the endogenous reactant?
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epoxide hydrolase (EH) in the microsomes and cytosol, uses water
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In glucuronidation, what are the types of substrates?
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phenols, alcohols, carboxylic acids, hydroxylamines, sulfonamides
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In acetylation, what are the types of substrates?
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amines
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In glutatione conjugation, what are the types of substrates?
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epoxides, arene oxides, nitro groups, hydroxylamines
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In glycine conjugation, what are the types of substrates?
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acyl-coa derivatives of carboxylic acids
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In sulfation, what are the types of substrates?
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phenols, alcohols, aromatic amines
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In methylation, what are the types of substrates?
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catecholamines, phenols, amines
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In water conjugation, what are the types of substrates in microsomes?
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arene oxides, cis-disubstituted and mono-substituted oxiranes
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In water conjugation, what are the types of substrates in the cytosol?
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alkene oxides, fatty acid epoxides
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What causes the slow acetylator phenotype?
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caused by the synthesis of less of the NAT2 enzyme
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What is associated with the slow acetylator phenotype?
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higher incidence of drug-induced autoimmune disorders and bicyclic aromatic amine-induced bladder cancer
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What are UGT-polymorphisms assosiated with?
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hyperbirubinemic diseases as well as impaired drug conjugation and/or elimination
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What P450 enzyme is affected in the debrisoquin-sparteine oxidation type of polymorphism?
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CYP2D6
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What P450 enzyme does the stereoselective aromatic 4-hydroxylation polymorphism involve, and what drug is affected?
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CYP2C19 of anticonvulsant mephenytoin
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What allele encodes for CYP2C9*2 and what is the impaired function?
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Arg144Cys mutation and impaired functional interactions with P450 reductase
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What allele encodes for CYP2C9*3 and what is the impaired function?
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Ile359Leu mutation and impaired affinity for many substrates
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What enzyme is responsible for nicotine oxidation?
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CYP2A6
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What is the correlation with tobacco smokers and low CYP2A6 activity?
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comsume less and have a lower incidence of lung cancer
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What foods are known to induce CYP1A enzymes?
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charcoal-broiled foods and cruciferous vegetables
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What is known to inhibit CYP3A metabolism of coadministered drug substrates?
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grapefruit juice
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Patients who ingest what other drugs require higher doses of warfarin?
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barbiturates, other sedative-hypnotics, or certain antipsychotic drugs
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What does tolerance mean in pharmacolokinetics?
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progressive reduced therapeutic effectiveness due to enhancement of their own metabolism
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What active component in grapefruit juice inactivates CYP3A4?
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furanocoumarins
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Where do furanocoumarins affect CYP3A4, what does it cause?
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intestinal mucosa and enhances its proteolytic degradation
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What drugs have an increased half life in patients with liver cirrhosis or acute viral hepatitis?
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chlorodiazepoxide and diazepam
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Bacterial/viral infections, cancer, or inflammation releases what to impair drug metabolism? And How?
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releases inflammatory mediators, cytokines, and nitric oxide by inactivating P450s and enhancing their degradation
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