Lecture 6: Metabolism

Question 1

Metabolism importance

Answer 1

-important determinant of duration and intensity
-alter activity of drugs
-influence half-life
-adverse drug effects

Question 2

2 reasons metabolism is important in drug reactions

Answer 2

-accumulation
-toxic metabolite

Question 3

Largest means of elimination of drugs

Answer 3

metabolism

Question 4

Sites of drug metabolism

Answer 4

-liver
-GI tract
-lungs
-kidney
-brain
-skin

Question 5

Liver

Answer 5

-smooth ER of liver cells
-high concentration of metabolizing enzymes
-first organ exposed to compounds from the gut

Question 6

Sites of Metabolism before drug enters systemic circulation

Answer 6

-small intestine
-liver

Question 7

Phase I of drug metabolism

Answer 7

-biotransformation to introduce or expose functional group for phase II reactions
-catalyxed by CYP using NADPH and oxygen

Question 8

Phase I reactions

Answer 8

-oxidation
-hydroxylation

Question 9

Phase II (Conjugation) of metabolism

Answer 9

-conjugation of polar group (acetyl, sulfate) with drug
-change charge and polarity

Question 10

Phase I metabolites

Answer 10

-excreted if polar
-or functionalized to undergo phase II

Question 11

Cytochrome P450

Answer 11

-membrane anchored
-heme group
-oxidation
-broad specificities

Question 12

P450 reductase

Answer 12

-coenzyme
-uses NADPH to provide reducing factors to P450

Question 13

2 ways to decrease CYP450 metabolism

Answer 13

-inhibit P450 reductase
-decrease NADPH
-decrease expression

Question 14

Nomenclature of CYPs

Answer 14

CYP[family][subfam][gene]*[allele]

CYP2D6*1A

Question 15

most important CYPs

Answer 15

-CYP3A4
-CYP2D6
-CYP2C8

Question 16

P450 substrates

Answer 16

-vast spectrum of diverse structures
-makes drug development hard

Question 17

Catalytic center of CYP450

Answer 17

-iron-heme cofactor
-iron binds to 4 N of heme, one thiolate ligand, or water in native state

Question 18

Light absorption of CYP450

Answer 18

-450nm
-upon reduction and carbon monoxide binding

Question 19

Reaction mechanism

Answer 19

1. substrate binds
2. 2 reducing equivalents
3. product

-many places to interfere this cycle
-iron catalytic site

Question 20

CYP450 inhibitors

Answer 20

-coordinate with iron to prevent metabolism

Question 21

CYP reactions

Answer 21

-Aromatic hydroxylation (OH)
-N-dealkylation (lose CH3 on N)
-O-dealkylation (lose CH3 on O)
-N-oxidation (and O to NR3)
-sulfoxidation (add =O to S)
-deamination

Question 22

Intrinsic factors determining CYP450 metabolism

Answer 22

-compund must enter binding site
-how does ligand bind
-how strong is binding
-reactivity of group in catalytic center
-accessibility of chemical group

Question 23

Reversible Inhibtion of CYP450

Answer 23

-compete for active site
-similar to antagonist

Question 24

Factors that determine binding strength

Answer 24

-coordination strength with heme
-hydrophobic contacts with binding site
-specific contacts with binding site residues

Question 25

Strong irreversible inhibitor

Answer 25

-molecules with Nitrogen as 6th iron-coordinating molecule
-additional hydrophobic contacts

Question 26

Ketoconazole

Answer 26

-antifungal
-serves as 6th ligand for CYP450
-potent inhibitor

Question 27

Erythromycin

Answer 27

-metabolite not substrate is inhibitor

Question 28

Inhibitor might not inhibit metabolism of ALL substrates

Answer 28

-competitive
-different binding site moieties
-inhibitor binds to a site, changes shape to prevent a substrate binding, another substrate can bind to another site

Question 29

Irreversible inhibition of CYP450

Answer 29

-mechanism-based inhibition (MBI)
-suicide inhibition

Question 30

Mechanism-based inhibition (MBI)

Answer 30

-metabolism generates reactive metabolite
-irreversibly interacts with heme or residues in binding site
= further metabolism of drug is delayed as CYP needs to be resynthesized

Question 31

CYP inducer

Answer 31

-decreases drug concentration

Question 32

CYP inhibitor

Answer 32

-increase drug concentration