Pharm I Drug Dispostion Iii (Metabolism)

Front 1

Why do drug companies care so much about drug metabolism?

Back 1

1. FDA required… 2. Know which metabolite are toxic, 3. Find out which metabolites are active and get patent

Front 2

Can one say whether metabolism will lead to activation or inactivation without more information?

Back 2

No, it can be either, depending on the drug

Front 3

Why is it important for physician to understand drug metabolism?

Back 3

a) prediction of drug-drug interaction, genetic variation… b) use alternate drug Rx with knowledge

Front 4

Why is it important that metabolism make a drug more polar?

Back 4

so that it will remain excreted after glomerular filtration or secretion into the intestines

Front 5

What are the two major biotransformation phases in drug metabolism?

Back 5

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

Front 6

Does phase I happen before phase II?

Back 6

Not always

Front 7

Name the Synthetic phase II (hint?)

Back 7

glucuronide formation,acetylation, sulfation, glycine congugation, and glutathione conjugation… (GAS GG-fcc)

Hint 7

(GAS GG)

Front 8

(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.

Back 8

(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 8

Hint: el HORD-OH

Front 9

Which phase I rxn is associated with toxic activation of aromatic amines?

Back 9

Hydroxylation (associated with chemical carcinogens)

Hint 9

None

Front 10

Which dealkylation rxn removes a methyl or ethyl group from a nitrogen atom

Back 10

N-Dealkylation

Front 11

Which dealkylation rxn removes a methyl or ethyl group from an oxygen atom

Back 11

O-dealkylation

Front 12

Which phase and rxn adds an oxygen to a sulfur atom? which phase and rxn adds an oxygen to a nitrogen atom?

Back 12

Phase I (CYP) S-oxidation rxn... Phase I (CYP) N-oxidation

Hint 12

None

Front 13

Which phase and rxn is a common catacholamine pathway?

Back 13

O-Methylation phase I, non-CYP

Front 14

Which phase and rxn is associated with non-specific esterases in the plasma and in cells?

Back 14

Hydrolysis in phase I… non-CYP

Front 15

Name 3 additional CYP rxns in phase I (hint?)

Back 15

DED: dechlorination, epoxidation, deamination

Hint 15

DED

Front 16

Which 3 cofactors are required in the Mixed Function Oxidase (CYP450) System Enzymes?

Back 16

Fe, O2, and NADPH (a specific flavoprotein containing both FAD and FMN)

Front 17

CYPs are ____-____ containing proteins.

Back 17

Fe heme

Front 18

What is the role of NADPH in mixed function oxidase (CYP450) system enzymes?

Back 18

Supplies electrons

Front 19

In which organelle do you find the activities of CYP 450s?

Back 19

smooth ER

Hint 19

None

Front 20

T/F The CYP 450 enzyme have many polymorphisms

Back 20

TRUE

Front 21

What are the 4 generalized steps involved in Mixed Function Oxidase (CYP) system drug rxns?

Back 21

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.

Front 22

T/F Individual CYP members do not have overlapping specificity.

Back 22

False, the have low and frequently overlapping specificity… which gives the collective CYPs a wide range of drugs they can metabolize

Front 23

What is the principle form of CYP found in the intestine.

Back 23

CYP3A4 is the principle form of CYP found in the intestine

Hint 23

None

Front 24

T/F The nasal mucosa have a small but present concentration of CYP

Back 24

False, it has one of the highest concentration of CYP

Front 25

Name for other 4 other phase I drug metabolizing enzymes. (These you already know)

Back 25

Esterases, amidases, epoxide hydrolase, and alcohol dehydrogenase

Hint 25

None

Front 26

Which of the congugation (synthesis) pathways of Phase II is most commonly seen?

Back 26

Glucuronide formation

Front 27

Describe the 2 steps in glucuronic formation

Back 27

Glucose --(UTP added w/ glucuronosyl transferase) --> Glucuronic acid --> added to substrate (Drug)

Front 28

NAT1 and NAT2 transferases are used in which Phase and pathway in drug metabolism?

Back 28

Phase II (synthesis): Acetylation

Front 29

_____ is a common pathway for aliphatic and aromatic primary amines and utilizes acetyl CoA as a co-substrate

Back 29

Acetylation, in phase II

Hint 29

None

Front 30

Steroid hormones are metabolized by which phase II metabolic pathway? What is required in this pathway?

Back 30

Sulfation… ATP

Front 31

Which phase and specific metabolic pathway would you find a glycine being added to the substrate (drug)?

Back 31

Glycine conjugation, in phase II

Front 32

Which is the major detoxifying (for drugs and toxins) metabolic mechanism found in the body… and which phase?

Back 32

Glutathione (GSH) conjugation in phase II

Front 33

In Glutathione conjugate formation, what is the final product N-acetyl-cysteinyl-conjugate known as?

Back 33

Mercapturic acid

Front 34

Which metabolic pathway is the only one that creates a less polar substrate?

Back 34

Acetylation in phase II

Front 35

Mercapturic acid excreted in the urine is a product of which metabolic pathway?

Back 35

glutathioine in phase II

Front 36

T/F GSH pathway (glutathione), aside from being the major detoxifying pathway, also activates drugs and some being toxic and carcinogenic

Back 36

TRUE

Front 37

What type of drug is excreted more readily, charged or uncharged?

Back 37

highly charged particles are renally excreted much easier.

Front 38

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?

Back 38

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 38

hint: CHAHD-DAN

Front 39

what is the major bacteria in the gut flora?

Back 39

obligate anaerobes, thus only pathways that don't require O2 are seen

Front 40

What can cause the reversal of phase II conjugation?

Back 40

Hydrolysis of a Drug-conjugate in the intestine --> followed by reabsorption Enterohepatic circulation and remove conjugate

Front 41

Elimination occurs by what order of kinetics?

Back 41

First order and is thus proportional to the amount of drug in the body

Front 42

How are drugs reabsorbed in the tubules? What criteria must be met for passive diffusion to occur?

Back 42

a) passive diffusion… b) they must be nonpolar to be reabsorbed… thus the metabolized polar drugs are efficiently excreted

Front 43

How can renal excretion of drugs be altered?

Back 43

changing pH via ion trapping

Front 44

Can renal excretion only be increased in the renal tubules?

Back 44

No, it can increased (for toxic compounds) or decreased.

Front 45

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?

Back 45

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

Front 46

What types of compounds are excreted by biliary system?

Back 46

highly polar and high molecular weight (>500)

Front 47

T/F some drugs excreted throught billiary tree are reabsorbed in the gut.

Back 47

TRUE

Front 48

Where was amionopyrine used? What was it replaced by?

Back 48

a) breath test (involving lung excretion and carbon 14 and 13) of the liver's metabolizing function… b) erythromycin

Front 49

What 4 factors effect drug entry in breast milk?

Back 49

a) drug pka, b) pH of milk and plasma, c) binding of drug to plasma and milk proteins, and c) fat composition of milk.

Hint 49

None

Front 50

What is the role of saliva in drug excretion?

Back 50

not a major route, but it may offer a method to monitor drug levels.