Lecture 4 (Drug Metabolism) Flashcards by Sam Myers

Main site in body for drug metabolism?

liver

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Liver is the site of ???

1st pass metabolism

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Where else can drugs be metabolized in the body?

secretion into bile
elimination in feces
kidneys (filter blood)
lungs (exhale drugs)
intestinal gut flora
skin and other organs

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Very hydrophilic drugs will get excreted ____

unchanged

they are already water soluble

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Lipophilic drugs are usually ______

metabolized

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Why do lipophilic drugs tend to be in the body longer than hydrophilic drugs?

1 - they need to be metabolized

2- lipophilic drugs can bind to proteins that are distributed in fatty tissues

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lipophilic drugs generally avoid excretion by _____

kidney

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goal of drug metabolism?

chemically modify (metabolize) lipophilic drugs to increase their water solubility so they can be excreted by the kidney

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Phase 1 metabolism?

drug becomes modified drug by:
-adding/exposing functional groups to make it more water soluble

oxidation (most common)
hydrolysis
reduction

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Phase 2 metabolism?

biosynthetic conjugation

modified drug transforms to drug-conjugated

Glucuronidation
Acetylation (glutathione)
Sulfation

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There are typically several routes of metabolism - why is this a good thing?

it is good that there is more than 1 route because if something affects one route - the drug will not accumulate in the body and pose a risk of potential toxicity

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cytochrome P450 family of enzymes referred to as ___

CYP enzymes

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CYP are ___ proteins that require electrons and molecular oxygen (O2) to function

heme

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where do the electrons come from

NADPH

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What is the general formula for Phase 1 CYP

R + NADPH + O2 + H+ —CYP–> R-OH + NADP+ + H2O

*R = drug

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CYP enzyme family is grouped by relatedness measured by ??

amino acid similarity

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CYP 1 through 4 are known as ?

drug metabolizing enzymes

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CYP 11, 17, 19, 21 are the ??

steroidogenic enzymes

*these also participate in drug metabolism of drugs that are steroid like in structure

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first number refers to _____

family (having > 40% amino acid similarity)

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letter refers to _____

subfamily (having > 59% amino acid similarity)

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last number refers to ____

subtype of subfamily

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CYP reactions:
aliphatic hydroxylation
(omega-1 hydroxylation)
(subterminal hydroxylation)

on “next to last” (penultimate) carbon on aliphatic chain
chain has to have 2 or more carbons

*carbon directly attached to an aromatic group more likely to be hydroxylated

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aliphatic hydroxylation:

longer the chain = ?

higher the rate

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CYP reactions:

aromatic hydroxylation

ED R groups tend to increase hydroxylation and favours para hydroxylation (where the OH and R are directly across from each other)

EW R groups tend to decrease hydroxylation

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In fused aromatic ring systems - usually only ___ ring will be hydroxylated

one

typically rings with _____ and __ groups will not be hydroxylated

halogens EW

``` CYP reactions: alkene oxidation (epoxidation) ```

epoxide is very reactive and may decompose non-enzymatically in H2O *alkene becomes an epoxide (three membered ring with O)

CYP reactions: | N or S oxidation

O is added to N or S

see slide 16 for: | N, O, or S dealkylation (v common)

ok man

CYP reactions: | deamination

see slide 16

What 3 ways can epoxides be hydrolyzed?

1) EH (epoxide hydrolase) or non-enzymatic 2) GST/ GSH (glutathione s transferase/ glutathione) 3) protein * See slide 17

describe the CYP enzyme active site

heme group attached to an active oxygen (very electron deficient and reactive) *oxygen is binded to the Fe2+ group and is converted into a reactive form

Substrate binding site generally prefers _____ substrates

hydrophobic | because we are trying to make it more hydrophilic

some drugs are CYP inhibitors and they have ____ groups on them that bind to the oxygen and inhibit the CYP enzymes

imidazole

??? are the most prominent example of CYP enzyme inhibitors

azole antifungals *they often also have large hydrophobic regions that bind to the CYP substrate binding pocket making them ideal CYP inhibitors

give 2 examples of azole antifungals

ketoconazole itraconazole *they are the most potent azole anti fungal inhibitors of CYP enzymes

_____ is also an inhibitor but less potent

fluconazole

Are esterases/amidases CYPs?

NO *but they do perform hydrolysis rxns and are Phase 1 enzymes

What are pro-drugs often designed as?

esters and amides - so then they can be hydrolyzed by esterases or amides to produce an active drug

What do Phase 2 enzymes require?

- substrate that is an unmodified drug or a drug modified by Phase 1 - require activated endogenous chemical (activated because it acts as a good leaving group for transfer of endogenous chemical to drug) - functional group on drug to modify

List the 6 types of Phase 2 conjugation

- glucuronide conjugation (most important) - glutathione conjugation - methylation - acetylation - sulfate conjugation - amino acid conjugation

Glucuronide conjugation: | enzyme?

UGT | UDP-glucuroosyltransferases

Glucuronide conjugation: | activated endogenous chemical?

UDP-GA | uridine diphosphate glucuronic acid

Glucuronide conjugation: | target functional groups?

OH ( most common) | SH, NH, COOH, R-NH-OH, R-S-OH

Glucuronide conjugation: | if product

excreted in urine

Glucuronide conjugation: | if product > 350 Da ?

excreted in feces

Glutathione conjugation: | enzyme?

GST | glutathione S transferase

Glutathione conjugation: | activated endogenous chemical?

GSH (yglutamyl-cystenyl-glycine) *this is not activated - therefore is an exception to the rule

Glutathione conjugation: | target functional groups?

any electrophile carbonyls substituted aromatic rings double bonds

Glutathione conjugation: | mostly excreted in ?

feces

Describe GST (glutathione S transferase)

- tripeptide found in all tissues - has a thiol group - toxic reactive metabolic intermediates of drugs are often detoxified by glutathione

Sulfate conjugation: | enzyme?

ST | sulfotransferase

Sulfate conjugation: | activated endogenous chemical?

PAPS | phosphoadenosine phosphosulfate

Sulfate conjugation: | target functional groups?

``` OH phenols catechols hydroxyl amines hydroxysteroids (estradiol) ```

Sulfate conjugation: | excreted in ?

urine

Methylation: | enzyme?

MTase | methytransferase

Methylation: | activated endogenous chemical?

SAM :) | S-adenosyl methionine

Methylation: | target functional groups?

O, N, S *this may reduce water solubility but it is more important biochemically to inactivate endogenous compounds

Methylation: | excretion ?

urine or feces

Acetylation: | enzyme?

AT (acetyl transferase) there can be NAT, OAT, or SAT NAT = most common

Acetylation: | activated endogenous chemical?

acetyl CoA | acetyl co enzyme A

Acetylation: | target functional groups?

mainly N sometimes O or S

Acetylation: | excreted in?

mostly urine

Amino acid conjugation: | enzyme?

AA-T (aminoacyl transferase) *most important in glycine

Amino acid conjugation: | activated endogenous chemical?

Drug-CoA *drug is activated usually through COOH

Amino acid conjugation: | target functional groups?

COOH

Amino acid conjugation: | mostly excreted in ?

urine