drugmetabolism

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Transcript drugmetabolism

11/06/08
11/11/08
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Drug Metabolism
or
What’s wrong with more grapefruit juice?
McGill University Health Centre Journal
Grapefruit and drugs a potent mix
Grapefruits are chalk full of vitamin C, potassium and natural fiber. So they have to
be good for you, right? Well, not necessarily.
Taking a swallow of grapefruit juice to down your prescription medication could play
havoc with the digestion of certain drugs, increasing the amount of medication
released into the bloodstream, which could lead to harmful levels or drug toxicity.
To complicate matters, if you have always enjoyed a glass of grapefruit juice,
stopping this habit could cause the opposite effect, your body will absorb too little
medication.
Drugs that interact with grapefruit juice.
Anxiety: Xanax, Buspar, Versed, Halcion
Depression: Luvox, Zoloft
Allergies: Allegra
Abnormal heart rhythm: Cordarone, quinidine
Heart disease/stroke/blood clots: Coumadin
Epilepsy: Tegretol
Cancer: Cyclophosphamide, etoposide, ifosfamide, tamoxifen, vinblastine, vincristine
Cough: Dextromethorphan
HIV: Agenerase, Crixivan, Viracept, Norvir, Fortovase
Heart disease/High blood pressure: Coreg, Cardizem, Plendil, Cardene, Adalat,
Procardia, Nimotop, Sular, Covera, Calan, Verelan
Asthma/Emphysema: Theophylline
High cholesterol: Lipitor, Lescol, Mevacor, Zocor
Pain: Alfenta, Duragesic, Actiq, Sufenta
Furocoumarins in grapefruit juice inhibit certain forms of cytochrome P450
Cytochrome P450
Enzyme found mostly in liver
Cytochrome P450 has a wide range of roles
-steroid hormone biosynthesis from cholesterol
-metabolism of xenobiotics-compounds which are not normally found in
the body
-Drugs
-Compounds in food produced by cooking (polyaromatic hydrocarbons,
also in tobacco smoke) or microorganisms
-typically organic molecules which are poorly soluble in water
Cytochrome P450 aids in the metabolism of xenobiotics by adding OH to
increase the water solubility of the compound
O2 + substrate + 2 electrons
HO-substrate + H2 O
The OH added by P450 can then be used to attach sulfate (SO42-) or a sugar.
The modified drug can be more readily removed by the kidney.
Because this enzyme catalyzes the addition of one oxygen atom, it is
termed a monooxygenase.
Cytochrome P450 contains heme.
N
N
Fe
N
N
Heme
The heme group is a cofactor which contains iron.
Different forms of heme are found in hemoglobins and proteins
known as cytochromes.
The iron in a heme can bind oxygen and transfer electrons.
Cytochrome P450
Cytochrome P450’s are integral membrane proteins found in the endoplasmic reticulummembrane network in cells
http://micro.magnet.fsu.edu/cells/endoplasmicreticulum/endoplasmicreticulum.html
Cytochrome P450
At least 57 different isozymes in humans, over 7700 forms in Nature
isozyme-catalytically and structurally similar but genetically
distinct enzymes-different genes and amino acid sequences
Different isozymes have different substrate specificities
Individuals have several alleles for P450’s and differ in which isozymes they
have
Since individuals have different combinations of P450’s, they differ in their response
to specific drugs
A subset of cytochrome P450’s can be induced, so that more is expressed upon
exposure to a compound.
Because of the number of different isozymes and their different substrates and
inhibitors, the metabolism of a drug can be altered if an individual takes a second
drug.
Some substrates of cytochrome P450 isozymes
1A2
2B6
2C8
2C19
2C9
2D6
2E1
3A4,5,7
amitriptyline
caffeine
clomipr amine
clozapine
cyclobenzaprine
estradiol
fluvoxamine
haloperidol
imipramine NDeMe
mexilletine
naproxen
olanzapine
ondansetron
phenacetin
acetaminophen
propranolol
riluzole
ropivacaine
tacrine
theophylline
tizanidine
verapamil
bupropion
cyclophosphamide
efavirenz
ifosfamide
methadone
paclitaxel
torsemide
amodiaquine
cerivastatin
repaglinide
Proton Pump
Inhibitors:
lansoprazole
omeprazole
pantoprazole
rabeprazole
ibuprofen
meloxicam
S-naproxen
piroxicam
suprofen
Beta Blockers:
Anesthetics:
enflurane
halothane
isoflurane
methoxyflurane
sevoflurane
erythromycin
telithromycin
Anti-epileptics:
diazepam
phenytoin(O)
S-mephenytoin
phenobarbitone
amitriptyline
carisoprodol
citalopram
chloramphenicol
clomipr amine
cyclophosphamide
hexobarbital
imipramine
indomethacin
R-mephobarbital
Oral
Hypoglycemic
Agents:
tolbutamide
glipizide
Angiotensin II
Blockers:
losartan
irbesartan
Sulfonylureas:
glyburide/
glibenclamide
glimepiride
tolbutamide
amitriptyline
clomipr amine
desipramine
imipramine
paroxetine
Benzodiazepines:
cyclosporine
tacrolimus (FK506)
haloperidol
HIV Antivirals
alprenolol
amphetamine
aripiprazole
atomoxetine
bufuralol
chlorpheniramine
chlorpromazine
codeine
Antihistamines:
astemizole
chlorpheniramine
terfenadine
fluvoxamine
lidocaine
metoclopramide
methoxyamphetam
ine
Calcium Channel
Blockers
HMG CoA
Reductase
Inhibitors:
atorvastatin
cerivastatin
Some inhibitors of cytochrome P450 isozymes
1A2
2B6
2C8
fluvoxamine
ciprofloxacin
thiotepa
ticlopidine
gemfibrozil
cimetidine
amiodarone
fluoroquinolones
furafylline
interferon
methoxsalen
mibefradil
2C19
lansoprazole
omeprazole2
trimethoprim pantoprazole
rabeprazole
glitazones
montelukast chloramphenicol
cimetidine
quercetin
felbamate
fluoxetine
fluvoxamine
indomethacin
ketoconazole
modafinil
oxcarbazepine
probenicid
ticlopidine
topiramate
3A4,5,7
2C9
2D6
2E1
fluconazole
bupropion
fluoxetine
paroxetine
quinidine
HIV Antivirals:
diethyldithiocarbamate indinavir
nelfinavir
ritonavir
duloxetine
terbinafine
clarithromycin
itraconazole
ketoconazole
nefazodone
saquinavir
telithromycin
amiodarone
fenofibrate
fluvastatin
fluvoxamine
isoniazid
lovastatin
phenylbutazone
probenicid
sertraline
sulfamethoxazole
sulfaphenazole
teniposide
voriconazole
zafirlukast
amiodarone
cimetidine
sertraline
celecoxib
chlorpheniramine
chlorpromazine
citalopram
clemastine
clomipramine
cocaine
diphenhydramine
doxepin
doxorubicin
escitalopram
halofantrine
hydroxyzine
levomepromazine
methadone
metoclopramide
mibefradil
aprepitant
erythromycin
fluconazole
grapefruit juice
verapamil
diltiazem
cimetidine
amiodarone
chloramphenicol
delaviridine
diethyldithiocarbamate
fluvoxamine
gestodene
Some inducers of cytochrome P450 isozymes
1A2
chromosome 15
2B6
chromosome 6
broccoli
phenobarbital
brussel sprouts
rifampin
char-grilled meat
insulin
methylcholanthrene
modafinil
nafcillin
beta-naphthoflavone1
omeprazole
tobacco
2C8
chromosome 10
2C19
chromosome 10
2C9
chromosome
10
2D6
chromosome 22
2E1
chromosome
10
3A4,5,7
chromosome 7
rifampin
carbamazepine
norethindrone
NOT pentobarbital
prednisone
rifampin
rifampin
secobarbital
dexamethasone
rifampin
thanol
isoniazid
HIV Antivirals:
efavirenz
nevirapine
barbiturates
carbamazepine
efavirenz
glucocorticoids
modafinil
nevirapine
oxcarbazepine
phenobarbital
phenytoin
pioglitazone
rifabutin
rifampin
St. John's wort
troglitazone
The reaction of cytochrome P450 can also produce a toxic compound:
Metabolism of acetaminophen (Tylenol)
O
C
HN
CH3
OH
Acetaminophen
At normal doses, sulfate or a sugar is attached to OH and the drug is easily
removed by the kidney.
At high doses, this pathway cannot keep up and a liver P450 converts acetaminophen
to a toxic metabolite which causes liver damage.
Metabolism of neurotransmitters-monoamine oxidase
Several important neurotransmitters are amines.
HO
HO
OH
HO
HO
NH3
dopamine
NH3
norepinephrine
HO
HO
NH3
NH3
HO
NH2
CH3
epinephrine
N
H
serotonin
These are released into the blood where they bind to receptors on
the surface of cells.
To ensure that the action of amine neurotransmitters is short, they are
destroyed by the enzyme monoamine oxidase.
Monoamines also come from the diet
Tyramine is formed from tyrosine. If blood levels rise they disrupt catecholamine
metabolism, leading to possibly fatal hypertension. Monoamine oxidase prevents
this.
HO
NH3
tyramine
Foods containing high levels of tyramine:
smoked, aged, or pickled meat or fish; sauerkraut
aged cheeses (e.g., swiss, cheddar, blue, boursault, camembert, emmenthaler, stilton);
yeast extracts
fava beans
beef or chicken liver
aged sausages (e.g., bologna, pepperoni, salami, summer sausage)
game meats (e.g., venison, rabbit)
red wines (e.g., chianti, sherry).
Monoamine oxidase
An integral membrane protein in liver mitochondria.
Oxidizes amines to aldehydes:
HO
O2
HO
HO
HO
NH3
O
+ NH4
Monoamine oxidase contains FAD as a cofactor
R'
N
N
O
NH
N
O
Flavin Adenosine Dinucleotide
Synthesized from the vitamin riboflavin
Used in electron transfer reactions
Monoamine oxidase contains FAD as a cofactor
Monoamine oxidase inhibitors
Monoamine oxidase (MAO) inhibitors are used as antidepressants and to
treat eating disorders.
They keep serotonin levels up. Serotonin controls mood.
MAO inhibitors can cause overdoses:
No longer break down tyramine from diet.
High levels of tryptophan in diet can result in serotonin levels becoming too high.
Will prevent metabolism of drugs that are amines. As a result MAO inhibitors can
result in serious side effects when used with other drugs.
MAO inhibitors have been replaced with drugs which prevent the binding of serotonin to cells,
such as Prozac. These do not affect the metabolism of other amines, so that there are far
fewer side effects.