Lecture 4 (Drug Metabolism) Flashcards
Main site in body for drug metabolism?
liver
Liver is the site of ???
1st pass metabolism
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
Very hydrophilic drugs will get excreted ____
unchanged
they are already water soluble
Lipophilic drugs are usually ______
metabolized
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
lipophilic drugs generally avoid excretion by _____
kidney
goal of drug metabolism?
chemically modify (metabolize) lipophilic drugs to increase their water solubility so they can be excreted by the kidney
Phase 1 metabolism?
drug becomes modified drug by:
-adding/exposing functional groups to make it more water soluble
oxidation (most common)
hydrolysis
reduction
Phase 2 metabolism?
biosynthetic conjugation
modified drug transforms to drug-conjugated
Glucuronidation
Acetylation (glutathione)
Sulfation
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
cytochrome P450 family of enzymes referred to as ___
CYP enzymes
CYP are ___ proteins that require electrons and molecular oxygen (O2) to function
heme
where do the electrons come from
NADPH
What is the general formula for Phase 1 CYP
R + NADPH + O2 + H+ —CYP–> R-OH + NADP+ + H2O
*R = drug
CYP enzyme family is grouped by relatedness measured by ??
amino acid similarity
CYP 1 through 4 are known as ?
drug metabolizing enzymes
CYP 11, 17, 19, 21 are the ??
steroidogenic enzymes
*these also participate in drug metabolism of drugs that are steroid like in structure
first number refers to _____
family (having > 40% amino acid similarity)
letter refers to _____
subfamily (having > 59% amino acid similarity)
last number refers to ____
subtype of subfamily
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
aliphatic hydroxylation:
longer the chain = ?
higher the rate
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
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
