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50 Cards in this Set

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  • Back
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Why do drug companies care so much about drug metabolism?
1. FDA required… 2. Know which metabolite are toxic, 3. Find out which metabolites are active and get patent
Can one say whether metabolism will lead to activation or inactivation without more information?
No, it can be either, depending on the drug
Why is it important for physician to understand drug metabolism?
a) prediction of drug-drug interaction, genetic variation… b) use alternate drug Rx with knowledge
Why is it important that metabolism make a drug more polar?
so that it will remain excreted after glomerular filtration or secretion into the intestines
What are the two major biotransformation phases in drug metabolism?
Phase I - Non-synthetic: drug remains same size but becomes more polar (hydroxylation)… Phase II - Synthetic: drug has a bulky group attached and becomes even more polar
Does phase I happen before phase II?
Not always
Name the Synthetic phase II (hint?)
glucuronide formation,acetylation, sulfation, glycine congugation, and glutathione conjugation… (GAS GG-fcc)
(GAS GG)
(1) Name the Major Oxidation and Reductive pathways in Phase I that are catalyzed by mixed function oxidase CYP 450s and the ones that are not catylized by the CYP 450s. (Hint?)

(2) (a/b) Which one is not seen much in the liver? Why? (c) Name two specific types of this rxn.
(1) CYP: Hydroxylation, Oxidation, Reduction and Dealkylation… non-CYP: O-methylation, Hydrolysis

(2) (a/b) Reduction reaction are inhibit by oxygen, so not seen much in Liver (c) Reduction of Azo and Nitro grous
Hint: el HORD-OH
Which phase I rxn is associated with toxic activation of aromatic amines?
Hydroxylation (associated with chemical carcinogens)
None
Which dealkylation rxn removes a methyl or ethyl group from a nitrogen atom
N-Dealkylation
Which dealkylation rxn removes a methyl or ethyl group from an oxygen atom
O-dealkylation
Which phase and rxn adds an oxygen to a sulfur atom? which phase and rxn adds an oxygen to a nitrogen atom?
Phase I (CYP) S-oxidation rxn... Phase I (CYP) N-oxidation
None
Which phase and rxn is a common catacholamine pathway?
O-Methylation phase I, non-CYP
Which phase and rxn is associated with non-specific esterases in the plasma and in cells?
Hydrolysis in phase I… non-CYP
Name 3 additional CYP rxns in phase I (hint?)
DED: dechlorination, epoxidation, deamination
DED
Which 3 cofactors are required in the Mixed Function Oxidase (CYP450) System Enzymes?
Fe, O2, and NADPH (a specific flavoprotein containing both FAD and FMN)
CYPs are ____-____ containing proteins.
Fe heme
What is the role of NADPH in mixed function oxidase (CYP450) system enzymes?
Supplies electrons
In which organelle do you find the activities of CYP 450s?
smooth ER
None
T/F The CYP 450 enzyme have many polymorphisms
TRUE
What are the 4 generalized steps involved in Mixed Function Oxidase (CYP) system drug rxns?
1. Drug binds to CYP in its oxidized 3+ state… 2. Reduction of the CYP-Drug complex by NADPH…(transferred by Flavoprotein)... 3. Oxygen binds to complex… 4. One atom of oxygen is inserted into drug the other into H2O.
T/F Individual CYP members do not have overlapping specificity.
False, the have low and frequently overlapping specificity… which gives the collective CYPs a wide range of drugs they can metabolize
What is the principle form of CYP found in the intestine.
CYP3A4 is the principle form of CYP found in the intestine
None
T/F The nasal mucosa have a small but present concentration of CYP
False, it has one of the highest concentration of CYP
Name for other 4 other phase I drug metabolizing enzymes. (These you already know)
Esterases, amidases, epoxide hydrolase, and alcohol dehydrogenase
None
Which of the congugation (synthesis) pathways of Phase II is most commonly seen?
Glucuronide formation
Describe the 2 steps in glucuronic formation
Glucose --(UTP added w/ glucuronosyl transferase) --> Glucuronic acid --> added to substrate (Drug)
NAT1 and NAT2 transferases are used in which Phase and pathway in drug metabolism?
Phase II (synthesis): Acetylation
_____ is a common pathway for aliphatic and aromatic primary amines and utilizes acetyl CoA as a co-substrate
Acetylation, in phase II
None
Steroid hormones are metabolized by which phase II metabolic pathway? What is required in this pathway?
Sulfation… ATP
Which phase and specific metabolic pathway would you find a glycine being added to the substrate (drug)?
Glycine conjugation, in phase II
Which is the major detoxifying (for drugs and toxins) metabolic mechanism found in the body… and which phase?
Glutathione (GSH) conjugation in phase II
In Glutathione conjugate formation, what is the final product N-acetyl-cysteinyl-conjugate known as?
Mercapturic acid
Which metabolic pathway is the only one that creates a less polar substrate?
Acetylation in phase II
Mercapturic acid excreted in the urine is a product of which metabolic pathway?
glutathioine in phase II
T/F GSH pathway (glutathione), aside from being the major detoxifying pathway, also activates drugs and some being toxic and carcinogenic
TRUE
What type of drug is excreted more readily, charged or uncharged?
highly charged particles are renally excreted much easier.
a) which 6 metabolic pathways are seen in gut flora? (Hint?)… b) what do all gut flora have in common in terms of metabolism of drugs? (c) Which of these pathways require an anaerobic environment?
Hyrolysis of conjugates,
hyrolysis of amides,
dehydroxylation,
deamination,
azo and nitro reduction…

b) none use oxygen because gut flora are obligate anaerobes…

(c) azo and nitro reduction
hint: CHAHD-DAN
what is the major bacteria in the gut flora?
obligate anaerobes, thus only pathways that don't require O2 are seen
What can cause the reversal of phase II conjugation?
Hydrolysis of a Drug-conjugate in the intestine --> followed by reabsorption Enterohepatic circulation and remove conjugate
Elimination occurs by what order of kinetics?
First order and is thus proportional to the amount of drug in the body
How are drugs reabsorbed in the tubules? What criteria must be met for passive diffusion to occur?
a) passive diffusion… b) they must be nonpolar to be reabsorbed… thus the metabolized polar drugs are efficiently excreted
How can renal excretion of drugs be altered?
changing pH via ion trapping
Can renal excretion only be increased in the renal tubules?
No, it can increased (for toxic compounds) or decreased.
a) How are organic anion and cation, bound to plasma proteins excreted into the tubular fluid of the proximal tubules? b) How does this understanding help explain the how we can maintain desired high plasma levels of given drugs?
a) Non-selective active transport by pumps in the proximal tubule of organic anions and some organic cations b) Inhibit the pumps, e.g., probenecid extends penicilin half-life in to several hours by competing with other drugs
What types of compounds are excreted by biliary system?
highly polar and high molecular weight (>500)
T/F some drugs excreted throught billiary tree are reabsorbed in the gut.
TRUE
Where was amionopyrine used? What was it replaced by?
a) breath test (involving lung excretion and carbon 14 and 13) of the liver's metabolizing function… b) erythromycin
What 4 factors effect drug entry in breast milk?
a) drug pka, b) pH of milk and plasma, c) binding of drug to plasma and milk proteins, and c) fat composition of milk.
None
What is the role of saliva in drug excretion?
not a major route, but it may offer a method to monitor drug levels.