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53 Cards in this Set

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