Download Drug Inter. - Dr.

Grapefruit Juice-Drug Interaction
Paul F. Cancalon
Florida Department of Citrus
http://www.wlap.org/wl-repository/umich/cacr/grand-rounds/20031202-annarbor-01-watkins/real/sld011.htm
P. B. Watkins 2003
Drug Blood Concentration (AUC)
Drug Taken with GJ
Drug Taken without GJ
Time
P. B. Watkins 2003
Cytochrome P450
Cytochrome P450 Definition
Cytochrome P450 enzymes are a superfamily of more than 160 known
members that play a major role in the metabolism a wide array of xenobiotics
including drugs, chemical carcinogens, insecticides, petroleum products, and
other environmental pollutants.
Although the liver is the primary organ for drug metabolism, extrahepatic
tissues such as lung, kidney and intestine, also play an important role for
detoxification or biotransformation of xenobiotics. Each tissue has a unique
P450 isozyme distribution and regulatory mechanism for cytochrome P450 gene
(CYP) expression.
Cytochrome P450 Naming
classification:
CYP 3 A 4 *15 A-B
family
isoenzyme allele
>40% sequencesub-family
homology
>55% sequencehomology
J R Oesterheld : Drug-Drug Interactions
Model of rat P450 2B1, showing mode of membrane attachment
home.ccr.cancer.gov
Lock/Key or Enzyme/Substrate
Reaction
Irreversible Inhibition
P-Glycoprotein
Cell Membrane
P Glycoprotein Blockage
www.biotechjournal.com
Furanocoumarins P450 Interactions
Furanocoumarins as potent chemical defenses
Furanocoumarins are toxic compounds found primarily in species of the
Apiaceae and Rutacea. They come in a variety of flavors and have adverse
affects on wide variety of organisms, ranging from bacteria to
mammals. Some of the furanocoumarins are photoactive--their toxicity is
enhanced in the presence of ultraviolet radiation..
The furanocoumarins found in wild parsnip play a dominant
role in resistance of this plant to its principal enemy the parsnip
webworm
May R. Berenbaum
Two potential outcomes of a coevolutionary interaction are an escalating arms race
Diversification of cytochrome P450 monooxygenases (P450s) is
thought to result from antagonistic interactions between plants and
their herbivorous enemies
Grapefruit Furanocoumarins
O
O
O
OH
O
OH
The immediate precursors for furanocoumarin synthesis are umbelliferone and
isoprene. Two categories of furanocoumarins are produced; the linear furanocoumarins
have the furan ring in line with the benz-2-pyrone nucleus, while the angular
furanocoumarins have the furan ring oriented at an angle to the nucleus.
O
O
O
O
O
O
O
O
O
O
OH
Bergapten
Bergaptol
O
O
O
O
Bergamottin
O
O
O
OH
O
O
O
OH
6,7-DHB
6,7-Epoxybergamottin
O
O
O
O
Paradisin C
O
O
Paradisin A
O
O
O
OH
OH
P. B. Watkins 2003
Spiro3,FC726,Paradisin
Bergamotin
3-4FC ?
Bergaptol
6,7 DHB
Up to 10 Spiroesters ?
FC ?
FC ?
FCs ?
040610Bergaptol_Bergamottin_Std_MSMS #356-364 RT: 5.02-5.12 AV: 5 NL: 1.00E5
T: + c ESI Full ms2 [email protected] [ 55.00-210.00]
159.1
100
95
90
85
80
O
75
O
70
O
65
OH
60
147.1
55
Bergaptol
50
45
40
175.0
35
131.1
30
203.2
25
20
160.1
15
10
148.3
132.1
5
103.2
158.6
142.1
118.9
161.5
176.1
174.1
204.2
183.8 186.8
0
60
70
80
90
100
110
120
130
m/z
140
150
160
170
180
190
202.2
200
210
040610Bergaptol_Bergamottin_Std_MSMS #2638-2644 RT: 34.95-35.02 AV: 4 NL: 2.50E7
T: + c ESI Full ms2 [email protected] [ 90.00-400.00]
203.2
100
O
95
O
90
O
85
OH
80
75
70
Bergaptol
65
60
55
O
O
O
50
45
O
40
35
30
Bergamottin
Geranyl side chain
25
20
15
10
243.3
137.1
5
0
229.0
109.1 135.5 137.8
100
150
271.1
202.6
200
250
m/z
283.1
297.1
300
321.1
339.1
359.9
350
379.2
400
0402Dihydroxybergamottin #20 RT: 0.42 AV: 1 NL: 1.82E5
T: + c ESI Full ms2 [email protected] [ 100.00-400.00]
354.8
100
95
90
85
80
75
O
70
O
O
O
O
65
O
60
OH
OH
55
O
50
203.2
OH
45
OH
Bergaptol
40
6,7-DHB
OH
35
30
25
20
15
153.0
10
337.0
135.0
5
0
100
170.9
243.4
203.8
120
140
160
180
200
220
240
259.8
260
m/z
335.5
280
300
320
352.6
350.7 355.6
340
360
372.0
373.1
380
395.3
400
0303PSL_Ruby_Juice_02 #1792 RT: 37.64 AV: 1 NL: 8.67E6
T: + c ESI Full ms [ 90.00-1500.00]
749.2
100
95
90
85
Spiroester3
80
75
O
70
O
O
65
60
O
55
Spiro3
50
Bergaptol
45
750.2
O
40
O
O
35
30
O
355.0
203.3
25
OH
O
372.8
20
726.9
OH
15
OH
792.0
OH
10
5
153.0
219.2
337.1
697.8
557.0 613.4
391.1 457.0 548.3
656.1
873.2 910.0 983.7
0
100
200
300
400
500
600
700
1473.6
793.1
800
m/z
900
1000
1095.1 1142.3 1185.2
1100
1200
1337.4 1389.0
1300
1400
1500
The order of inhibitory potency of these compou nds was
FC726>6,7DHBG>bergamottin> bergapten> bergaptol
Ohnishi A et al. : Br J Pharmacol. 2000 Jul;130(6):1369-77.
O
>
O
O
>
O
OH
O
O
O
>
O
O
O
O
O
OH
bergapten
6,7 DHB
Paradisin A
(Spiro 3)
bergamottin
>
O
O
O
OH
bergaptol
Drug Bioavailability
Uptake of orally administered drug proceeds after the stomach
passage via the small intestine.
In the gut and liver, a series of metabolic transformation occurs.
J R Oesterheld : Drug-Drug Interactions
www.siumed.edu/~dking2/ erg/images
arbl.cvmbs.colostate.edu/.../ smallgut/villus
Site of Action of Some Drugs
Affected by Grapefruit Juice
Calcium channel blockers
Target
Blocked - calcium channel blockers in actionwww.thediabetesvillage.com
Blocked - calcium channel blockers in actionwww.thediabetesvillage.com
Calcium channel blockers
decreases contractility in myocardial cells
and tone in vascular smooth muscle
www.soton.ac.uk
Drug- Grapefruit Juice Interaction
P. B. Watkins 2003
P. B. Watkins 2003
Time-course of recovery of CYP3A function after single doses of grapefruit juice.
Greenblatt DJ, von Moltke LL, Harmatz JS, Chen G, Weemhoff JL, Jen C, Kelley CJ, LeDuc BW and Zinny MA.
Clinical Pharmacology and Therapeutics 2003;74:121-12
Liver microsome method
microsome
Artefactual spherical particle, not present in the living cell, derived from
pieces of the endoplasmic reticulum present in homogenates of tissues or
cells: microsomes sediment from such homogenates when centrifuged at
10 6 g and higher: the microsomal fraction obtained in this way is often
used as a source of mono-oxygenase enzymes
micro.magnet.fsu.edu
Paradisin C: a new CYP3A4 inhibitor from grapefruit juice
Tetrahedron 58 (2002) 6631-6635Tetrahedron 58 (2002) 6631-6635
CYP3A4 inhibition assay
CYPP3A4 activity is based on nifedipine oxidation.
100 mM phosphate buffer (pH 7.4) containing 50 uM nifedipine 5 mM glucose-6-phosphate,
0.5 mM 3-NADP+, glucose-6phosphate dehydrogenase.
CYP3A4 is preincubated in 7 uL of the buffer at 37EC for 5 min and added to the sample
solution
The solution is incubated at 37EC for 1 h.
The residue is analyzed by reverse phase HPLC for the nifedipine metabolite (nifedipine
pyridine), and for nifedipine.
The value of IC50, the concentration required for 50% inhibition of CYP3A4 activity.
Liver
10%
Drug
Drug
100%
CYP3A4
80%
Drug
Small Intestine
20%
Drug
10%
Target
over 90% of saquinavir is metabolized by the
cytochrome P450 isoenzyme CYP3A4 {01} .
Saquinavir is thought to undergo extensive
first-pass
metabolism
and
is
rapidly
metabolized to a variety of inactive monoand di-hydroxylated compounds
Drug
100%
Drug
Drug
30%
Nucleus
CYP3A4
Drug
70%
Drug
?
Enterocytes
Villus
P Glycoprotein
FC
Drug
100%
Drug
Drug
70%
Nucleus
FCCYP3A4
Drug
30%
X
Enterocytes
Villus
P Glycoprotein
?
CYP3A4
Nucleus
FC
FC
Competitive Enzyme/Substrate Binding
Enterocyte
From: P. B. Watkins 2003
Nucleus
CYP3A4
FC Metab
FC Metab
FC Metab
Enzymatic Metabolism of FC (1h)
Enterocyte
From: P. B. Watkins 2003
Nucleus
CYP3A4
FC Metab
FC Metab
FC Metab
Protein Catabolism
Enterocyte
CYP3A4 Tagging and Destruction (3D)
From: P. B. Watkins 2003
P. B. Watkins 2003
Variation of Enterocyte CYP3A4 Activity
And the Oral Distribution of Substrates
CYP3A4 Activity
Drug Blood Concentration
10
0
CYP3A4 Distribution in Human Population
From: P. B. Watkins 2003
Time
P. B. Watkins 2003
Conclusions
What are the active compounds DHB or its metabolites?
Are P-glycoproteins involved in GJ/Drug Interactions ?
Is the liver involved in GJ/Drug Inter and
do CYP3A4 and Pgly act similarly in the intestine & the liver ?
Are most GJ/Drug Interactions problems factored in
during drug testing ?
Information Gathering
Potential Drug Interactions With Grapefruit
Lead author: William A. Kehoe, Pharm.D., MA,
Drug(s)
Findings
Implications
Amiodarone (Cordarone)
Increases blood levels of the drug.
Watch for irregular heart rhythm.
Alprazolam (Xanax)
Diazepam (Valium)
Midazolam (Versed)
Triazolam (Halcion)
Increases blood concentrations by
inhibiting the intestinal metabolism.
Watch for possible increased sedation. Clinical
significance on cognitive function is not known.
One reference indicates alprazolam may have a
small or negligible effect.
Buspirone (BuSpar)
Increases absorption and blood
concentrations.
Despite significant effects, the action of the drug
does not appear to be affected significantly.
Caffeine
Decreases caffeine metabolism.
Watch for possible increase in side effects, such as
nervousness or insomnia.
Amlodipine (Norvasc)
Diltiazem (Cardizem)
Felodipine (Plendil)
Nicardipine (Cardene)
Nifedipine (Procardia, Adalat)
Nimodipine (Nimotop)
Nisoldipine (Sular)
Verapamil (Calan, Verelan)
Increases blood concentrations, most
likely the result of grapefruit inhibiting the
intestinal metabolism.
Look for signs of toxicity, such as flushing,
headache, fast heart rate, and low blood pressure.
Some references dispute the clinical relevance of the
interactions with amlodipine, diltiazem, and
verapamil. However, there is considerable
interindividual variability in the effect of grapefruit on
drug metabolism.
Carbamazepine (Tegretol)
Increases blood concentrations.
Look for signs of toxicity, such as dizziness, poor
balance and coordination, drowsiness, nausea,
vomiting, tremor, and agitation.
Drug(s)
Findings
Implications
Carvedilol (Coreg)
Increases blood levels.
The clinical significance of this interaction is
not known.
Cyclosporine (Neoral, Sandimmune)
Increases blood concentrations.
Look for signs of toxicity, such as kidney and
liver damage, and immune suppression.
Estrogens
Increases absorption and blood
concentrations.
Effects are unknown at this time.
Fexofenadine (Allegra)
Might decrease oral absorption and
blood levels.
The clinical significance of this interaction is
unknown. Tell patients it’s best to take
fexofenadine with a plain glass of water.
Atorvastatin (Lipitor)
Lovastatin (Mevacor)
Simvastatin (Zocor)
Increases absorption and blood
concentrations. Grapefruit interaction
unlikely with pravastatin (Pravachol) or
fluvastatin (Lescol).
Look for increased toxicity, such as headache,
GI complaints, and muscle pain.
Itraconazole (Sporanox)
Impairs absorption.
Losartan (Cozaar)
Might reduce the blood levels of the
drug.
Methylprednisolone (cortisone)
Increases plasma concentration ofl
methylprednisolone.
The clinical significance of this interaction is
not known. Theoretically it could decrease
efficacy of itraconazole.
Might reduce the effectiveness of losartan, but
further studies are needed to determine
significance.
Consumption of large amounts of grapefruit
might increase the risk of adverse effects.
Quinidine
Decreases drug elimination.
The clinical significance of this interaction is
unknown.
Sertraline (Zoloft)
Increases serum concentrations.
The clinical significance of this interaction is
unknown
P450 DRUG-INTERACTIONS TABLE
Substrates
1A2
2B6
2C19
2C9
2D6
2E1
3A4,5,7
amitriptyline
caffeine
clomipramine
clozapine
cyclobenzaprine
estradiol
fluvoxamine
haloperidol
imipramine N-DeMe
mexiletine
naproxen
ondansetron
phenacetin=>
acetaminophen=>NAP
QI
propranolol
riluzole
ropivacaine
tacrine
theophylline
verapamil
(R)warfarin
zileuton
zolmitriptan
bupropion
cyclophosphamid
e
efavirenz
ifosfamide
methadone
Proton Pump
Inhibitors:
lansoprazole
omeprazole
pantoprazole
E-3810
NSAIDs:
diclofenac
ibuprofen
meloxicam
Snaproxen=>N
or
piroxicam
suprofen
Beta Blockers:
carvedilol
S-metoprolol
propafenone
timolol
Anesthetics:
enflurane
halothane
isoflurane
methoxyfluran
e
sevoflurane
Macrolide
antibiotics:
clarithromycin
erythromycin (not
3A5)
NOT
azithromycin
acetaminophe
n
=>NAPQI
aniline
benzene
chlorzoxazon
e
ethanol
N,N-dimethyl
formamide
theophylline
=>8-OH
Anti-arrhythmics:
quinidine=>3-OH
(not 3A5)
Anti-epileptics:
diazepam=>Nor
phenytoin(O)
S-mephenytoin
phenobarbitone
amitriptyline
carisoprodol
citalopram
clomipramine
cyclophosphamid
e
hexobarbital
imipramine NDeME
indomethacin
R-mephobarbital
moclobemide
nelfinavir
nilutamide
primidone
progesterone
proguanil
propranolol
teniposide
R-warfarin=>8OH
Oral
Hypoglycemic
Agents:
tolbutamide
glipizide
Angiotensin II
Blockers:
losartan
irbesartan
amitriptyline
celecoxib
fluoxetine
fluvastatin
glyburide
phenytoin=>4OH
rosiglitazone
tamoxifen
torsemide
S-warfarin
Antidepressants:
amitriptyline
clomipramine
desipramine
imipramine
paroxetine
Antipsychotics:
haloperidol
perphenazine
risperidone=>9OH
thioridazine
alprenolol
amphetamine
bufuralol
chlorpheniramine
chlorpromazine
codeine (=>OdesMe)
debrisoquine
dexfenfluramine
dextromethorphan
encainide
flecainide
fluoxetine
fluvoxamine
lidocaine
metoclopramide
methoxyamphetamin
e
mexiletine
nortriptyline
minaprine
ondansetron
perhexiline
phenacetin
phenformin
propranolol
quanoxan
sparteine
tamoxifen
tramadol
venlafaxine
Benzodiazepines
:
alprazolam
diazepam=>3OH
midazolam
triazolam
Immune
Modulators:
cyclosporine
tacrolimus
(FK506)
HIV Antivirals:
indinavir
nelfinavir
ritonavir
saquinavir
Prokinetic:
cisapride
Antihistamines:
astemizole
chlorpheniramine
terfenidine
Calcium Channel
Blockers:
amlodipine
diltiazem
felodipine
lercanidipine
nifedipine
nisoldipine
nitrendipine
verapamil
HMG CoA
Reductase
Inhibitors:
atorvastatin
cerivastatin
lovastatin
NOT pravastatin
simvastatin
Steroid 6betaOH:
estradiol
hydrocortisone
progesterone
testosterone
Miscellaneous:
alfentanyl
buspirone
cafergot
caffeine=>TMU
cocaine
dapsone
codeine- Ndemethylation
dextromethorpha
n
eplerenone
fentanyl
finasteride
gleevec
haloperidol
irinotecan
LAAM
lidocaine
methadone
odanestron
pimozide
propranolol
quinine
salmeterol
sildenafil
sirolimus
tamoxifen
taxol
terfenadine
trazodone
vincristine
zaleplon
zolpidem
Inhibitors
1A2
2B6
2C19
2C9
2D6
2E1
3A4,5,7
amiodarone
cimetidine
fluoroquinolones
fluvoxamine
furafylline
interferon?
methoxsalen
mibefradil
ticlopidine
thiotepa
ticlopidine
cimetidine
felbamate
fluoxetine
fluvoxamine
indomethacin
ketoconazole
lansoprazole
modafinil
omeprazole
paroxetine
probenicid
ticlopidine
topiramate
amiodarone
fluconazole
fluvastatin
fluvoxamine
isoniazid
lovastatin
paroxetine
phenylbutazone
probenicid
sertraline
sulfamethoxazole
sulfaphenazole
teniposide
trimethoprim
zafirlukast
amiodarone
buproprion
celecoxib
chlorpromazine
chlorpheniramine
cimetidine
clomipramine
cocaine
doxorubicin
fluoxetine
halofantrine
red-haloperidol
levomepromazine
metoclopramide
methadone
mibefradil
moclobemide
paroxetine
quinidine
ranitidine
ritonavir
sertraline
terbinafine
dithiocarbamat
e
disulfiram
HIV Antivirals:
delaviridine
indinavir
nelfinavir
ritonavir
saquinavir
amiodarone
NOT
azithromycin
cimetidine
ciprofloxacin
clarithromycin
diethyldithiocarbamate
diltiazem
erythromycin
fluconazole
fluvoxamine
gestodene
grapefruit juice
itraconazole
ketoconazole
mifepristone
nefazodone
norfloxacin
norfluoxetine
mibefradil
verapamil
DHB
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