Transcript 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 Taken with GJ Drug Taken without GJ
Time
P. B. Watkins 2003
Cytochrome P450
Cytochrome P450 Definition
Cytochrome P450 enzymes
members that are a superfamily of more than 160 known 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 >40% sequence homology sub-family >55% sequence homology allele 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 OH
Bergaptol
O O O O
6,7
-
DHB
OH OH O O
Bergapten
O O O O O O O O O
Bergamottin
O O
6,7-Epoxybergamottin
Paradisin A
O O O O O O O
Paradisin C
O O OH OH
P. B. Watkins 2003
FCs ?
15 10 5 0 35 30 25 20 55 50 45 40 75 70 65 60 040610Bergaptol_Bergamottin_Std_MSMS # 356-364 T: + c ESI Full ms2 [email protected] [ 55.00-210.00] RT: 5.02-5.12
AV: 5 NL: 1.00E5
100 95 90 85 80 103.2
118.9
60 70 80 90 100 110 120 131.1
132.1
130 m/z 142.1
140 147.1
148.3
150 159.1
160.1
158.6
161.5
160 175.0
174.1
170 O OH Bergaptol 176.1
183.8
186.8
180 190 O 203.2
202.2
204.2
200 O 210
15 10 5 0 45 40 35 30 25 20 040610Bergaptol_Bergamottin_Std_MSMS # 2638-2644 T: + c ESI Full ms2 [email protected] [ 90.00-400.00] 203.2
100 RT: 34.95-35.02
O 95 O 90 AV: 4 NL: 2.50E7
O 85 OH 80 75 70 65 60 55 50
Bergaptol
O Geranyl side chain 109.1
137.1
135.5
137.8
100 150 202.6
200 O O O
Bergamottin
229.0
243.3
250 m/z 271.1
283.1
297.1
321.1
339.1
300 350 359.9
379.2
400
0402Dihydroxybergamottin # 20 T: RT: 0.42
AV: 1 NL: + c ESI Full ms2 [email protected] [ 100.00-400.00] 1.82E5
100 95 90 85 80 35 30 25 20 15 10 5 0 100 55 50 45 40 75 70 65 60 120 135.0
140 153.0
160 OH OH 170.9
180 O 203.2
200 OH 203.8
220 O O
Bergaptol
243.4
259.8
240 m/z 260 280 O O 354.8
O O OH
6,7-DHB
OH 300 320 337.0
335.5
352.6
350.7
355.6
372.0
373.1
340 360 380 395.3
400
0303PSL_Ruby_Juice_02 # 1792 T: + c ESI Full ms [ 90.00-1500.00] RT: 37.64
AV: 1 NL: 8.67E6
100 749.2
95 90 85 80 75 70 65 60
Spiroester3
O O O O 55 50 45 40 35
Bergaptol
Spiro3 750.2
O O O 30 25 20 203.3
OH 15 10 5 0 100 153.0
OH 200 219.2
337.1
300 355.0
372.8
391.1
400 457.0
500 600 726.9
557.0
548.3
613.4
656.1
697.8
700 792.0
793.1
800 m/z 900 O 873.2
910.0
983.7
1000 O 1095.1
1142.3
1185.2
1100 1200 OH OH 1337.4
1300 1389.0
1400 1473.6
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 OH > O O O O > O O O O
bergapten
> O OH O O
bergaptol 6,7 DHB bergamottin Paradisin A (Spiro 3)
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
arbl.cvmbs.colostate.edu/.../ smallgut/villus www.siumed.edu/~dking2/ erg/images
Site of Action of Some Drugs Affected by Grapefruit Juice
Target
Calcium channel blockers
Blocked - calcium channel blockers in action www.thediabetesvillage.com
Blocked - calcium channel blockers in action www.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
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 37
E
C for 5 min and added to the sample solution The solution is incubated at 37
E
C 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 and di-hydroxylated compounds is rapidly metabolized to a variety of inactive mono-
Drug 30%
Nucleus
Drug
CYP3A4
Drug 70% Drug
P Glycoprotein ?
Enterocytes
Drug 100%
Villus
Drug 70%
Villus FC
Drug 100% Drug
Nucleus Enterocytes
FC
CYP3A4
Drug 30% X
P Glycoprotein ?
FC Nucleus Competitive Enzyme/Substrate Binding FC
From: P. B. Watkins 2003
Enterocyte
FC Metab Nucleus FC Metab FC Metab Enzymatic Metabolism of FC (1h)
From: P. B. Watkins 2003
Enterocyte
FC Metab Nucleus FC Metab FC Metab
Protein Catabolism
Enterocyte CYP3A4 Tagging and Destruction (3D)
From: P. B. Watkins 2003
P. B. Watkins 2003
10
Variation of Enterocyte CYP3A4 Activity And the Oral Distribution of Substrates
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
) Alprazolam (
Xanax
) Diazepam (
Valium
) Midazolam (
Versed
) Triazolam (
Halcion
) Increases blood levels of the drug.
Increases blood concentrations by inhibiting the intestinal metabolism.
Watch for irregular heart rhythm.
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
) Caffeine Amlodipine (
Norvasc
) Diltiazem (
Cardizem
) Felodipine (
Plendil
) Nicardipine (
Cardene
) Nifedipine (
Procardia
,
Adalat
) Nimodipine (
Nimotop
) Nisoldipine (
Sular
) Verapamil (
Calan
,
Verelan
) Increases absorption and blood concentrations.
Decreases caffeine metabolism.
Increases blood concentrations, most likely the result of grapefruit inhibiting the intestinal metabolism.
Despite significant effects, the action of the drug does not appear to be affected significantly.
Watch for possible increase in side effects, such as nervousness or insomnia.
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)
Carvedilol (
Coreg
) Cyclosporine (
Neoral
,
Sandimmune
) Estrogens Fexofenadine (
Allegra
) Atorvastatin (
Lipitor
) Lovastatin (
Mevacor
) Simvastatin (
Zocor
) Itraconazole (
Sporanox
) Losartan (
Cozaar
) Methylprednisolone (cortisone) Quinidine Sertraline (
Zoloft
)
Findings Implications
Increases blood levels.
Increases blood concentrations.
The clinical significance of this interaction is not known.
Look for signs of toxicity, such as kidney and liver damage, and immune suppression.
Increases absorption and blood concentrations.
Might decrease oral absorption and blood levels.
Increases absorption and blood concentrations. Grapefruit interaction unlikely with pravastatin (
Pravachol
) or fluvastatin (
Lescol
).
Impairs absorption.
Might reduce the blood levels of the drug.
Increases plasma concentration ofl methylprednisolone.
Decreases drug elimination.
Increases serum concentrations.
Effects are unknown at this time.
The clinical significance of this interaction is unknown. Tell patients it’s best to take fexofenadine with a plain glass of water.
Look for increased toxicity, such as headache, GI complaints, and muscle pain.
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.
The clinical significance of this interaction is unknown.
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 Anti-epileptics: diazepam=>Nor phenytoin(O) S-mephenytoin phenobarbitone amitriptyline carisoprodol citalopram clomipramine cyclophosphamid e hexobarbital imipramine N DeME indomethacin R-mephobarbital moclobemide nelfinavir nilutamide primidone progesterone proguanil propranolol teniposide R-warfarin=>8 OH NSAIDs: diclofenac ibuprofen meloxicam S naproxen=>N or piroxicam suprofen Oral Hypoglycemic Agents: tolbutamide glipizide Angiotensin II Blockers: losartan irbesartan amitriptyline celecoxib fluoxetine fluvastatin glyburide phenytoin=>4 OH rosiglitazone tamoxifen torsemide S-warfarin Beta Blockers: carvedilol S-metoprolol propafenone timolol Antidepressants: amitriptyline clomipramine desipramine imipramine paroxetine Antipsychotics: haloperidol perphenazine risperidone =>9OH thioridazine alprenolol amphetamine bufuralol chlorpheniramine chlorpromazine codeine (=>O desMe) debrisoquine dexfenfluramine dextromethorphan encainide flecainide fluoxetine fluvoxamine lidocaine metoclopramide methoxyamphetamin e mexiletine nortriptyline minaprine ondansetron perhexiline phenacetin phenformin propranolol quanoxan sparteine tamoxifen tramadol venlafaxine Anesthetics: enflurane halothane isoflurane methoxyfluran e sevoflurane acetaminophe n =>NAPQI aniline benzene chlorzoxazon e ethanol N,N-dimethyl formamide theophylline =>8-OH Macrolide antibiotics: clarithromycin erythromycin (not 3A5) NOT azithromycin Anti-arrhythmics: quinidine =>3-OH (not 3A5) 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 6beta OH: estradiol hydrocortisone progesterone testosterone Miscellaneous: alfentanyl buspirone cafergot caffeine=>TMU cocaine dapsone codeine- N demethylation 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 amiodarone cimetidine fluoroquinolones fluvoxamine furafylline interferon?
methoxsalen mibefradil ticlopidine 2B6 thiotepa ticlopidine 2C19 cimetidine felbamate fluoxetine fluvoxamine indomethacin ketoconazole lansoprazole modafinil omeprazole paroxetine probenicid ticlopidine topiramate 2C9 2D6 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 2E1 3A4,5,7 dithiocarbamat e disulfiram HIV Antivirals: delaviridine indinavir nelfinavir ritonavir saquinavir amiodarone NOT azithromycin cimetidine ciprofloxacin clarithromycin diethyl dithiocarbamate diltiazem erythromycin fluconazole fluvoxamine gestodene grapefruit juice itraconazole ketoconazole mifepristone nefazodone norfloxacin norfluoxetine mibefradil verapamil
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