CYP3A4,5,7底物 抑制剂 诱导剂

Cytochrome P450

Drug Interactions Table

Use of this Table:

• Definitions

Substrates: drugs that are metabolized as substrates by the

enzyme

Inhibitors: drugs that prevent the enzyme from metabolizing

the substrates

Activators: drugs that increase the enzyme’s ability to

metabolize the substrates

• The table contains lists of drugs in columns under the

designation of specific cytochrome P450 isoforms. A drug

appears in a column if there is published evidence that it is

metabolized, at least in part, via that isoform. It does not

necessarily follow that the isoform is the principal metabolic

pathway in vivo, or that alterations in the rate of the

metabolic reaction catalyzed by that isoform will have large

effects on the pharmacokinetics of the drug.

• This P450 table was taken from the website

/flockhart/ and is maintained by

David A. Flockhart, MD, PhD, in the Division of Clinical

Pharmacology at Indiana University School of Medicine.

This table is intended to be used as an educational tool. For

specific literature references to drugs in this table, please

refer to Website /flockhart/.

The information was obtained from the above website on July

19, 2004. This web page is updated as new information

becomes available.

Substrates

1A2

amitriptyline

caffeine

clomipramine

clozapine

cyclobenzaprine

(Flexeril®)

estradiol

flovoxamine

haloperidol

imipramineN-DeMe

mexiletine

naproxen

olanzapine

ondansetron

phenacetin=>acetaminophen

=>NAPQI

propanolol

riluzole

ropivacaine

tacrine

theophylline

verapamil

(R)warfarin

zileuton

zolmitriptan

2B6

bupropion

cyclophosphamide

efavirenz

ifosfamide

methadone

2C8

paclitaxel

torsemide

amodiaquine

cerivastatin

repaglinide

2C19

Proton Pump

Inhibitors:

omeprazole

lansoprazole

pantoprazole

E-3810

2C9

NSAIDs:

diclofenac

ibuprofen

meloxicam

S-naproxen=>Nor

piroxicam

suprofen

2D6

Beta Blockers:

carvedilol

S-metoprolol

propafenone

timolol

2E1

Anesthetics:

enflurane

halothane

isoflurane

methoxyflurame

sevoflurane

3A4,5,7

Macrolide Antibiotics:

clarithromycin

erythromycin (not 3A5)

NOT azithromycin

Anti-arrhythmics:

quinidine=>3-OH

(not 3A5)

Antidepressants:

amitriptyline

clomipramine

desipramine

imipramine

paroxetine

Oral Hypoglycemic

Agents:

tolbutamide

glipizide

Benzodiazepines:

alprazolam

diazepam=>3OH

midazolam

triazolam

Acetaminophen

=>NAPQI

aniline

benzene

chlorzoxazone

ethanol

N,N-dimethyl

Formamide

theophylline=>8-

OH

Immune Modulators:

cyclosporine

tacrolimus(FK506)

Anti-epileptics:

diazepam=>Nor

phenytoin(O)

S-mephenytoin

phenobarbitone

Angiotensin II

Blockers:

irbesartan

losartan

Sulfonylureas:

Glyburide

Glibenclamide

Glipizide

Glimepiride

tolbutamide

Antipsychotics:

haloperidol

perphanazine

risperidone=>9O

H

thioridazine

amiptriptyline

carisoprodol

citalopram

clomipramine

cyclophosphamide

hexobarbital

imipramine N-DeMe

indomethacin

R-mephobarbital

moclobemide

nelfinavir

nilutamide

primidone

progesterone

proguanil

propranolol

teniposide

R-warfarin=>8-O

H

amitriptyline

celecoxib

fluoxetine

fluvastatin

glyburide

nateglinide

phenytoin=>4-OH

rosiglitazone

tamoxifen

torsemide

S-warfarin

alprenolol

amphetamine

atomoxetine

bufuralol

chlorpheniramine

chlorpromazine

codeine (=>O-desMe)

debrisoquine

dexfenfluramine

dextromethorphan

ecainide

flecainide

fluoxetine

fluvoxamine

lidocaine

metoclopramide

methoxyamphetamine

mexiletine

nortriptyline

minaprine

ondansetron

perhexiline

HIV Antivirals:

indinavir

nelfinavir

ritonavir

saquinavir

Prokinetic:

cisapride

Antihistamines:

astemizole

chlorpheniramine

terfenidine

Calcium Channel Blockers:

amlodipine

diltiazem

felodipine

lercanidpine

nifedipine

nisoldipine

nitrendipine

verapamil

Substrates Continued

1A2

2B6

2C8

2C19

2C9 2D6

phenacetin

phenformin

propranolol(=>4OH)

sparteine

tamoxifen

tramadol

venlafaxine

2E1

3A4,5,7

HMG CoA Reductase

Inhibitors

atorvastatin

cerivastatin

lovastatin

NOT pravastatin

simvastatin

Steroid 6beta-OH

estradiol

hydrocortisone

progesterone

testosterone

Miscellaneous

alfentanyl

buspirone

cafergot

caffiene=>TMU

cocaine

dapsone

codeine-N

demethylation

dextromethophan

eplerenone

fentanyl

finasteride

gleevec

haloperidol

irinotecan

LAAM

lidocaine

methadone

nateglinide

odanestron

pimozide

propranolol

quinie

Not rosuvastatin

salmeterol

sildenafil

sirolimus

tamoxifen

taxol

terfenadine

trazodone

vincristine

zaleplon

zolpidem

Inhibitors

1A2

amiodarone

cimetidine

fluoroquinolones

fluvoxamine

furafylline

interferon?

methoxsalen

mibefradil

ticlopidine

thiotepa

2B6 2C8

trimethoprim

quercetin

glitazones

gemfibrozil

2C19

cimetidine

felbamate

fluoxetine

fluvoxamine

indomethacin

ketoconazole

lansoprazole

modafinil omeprazole

paroxetine

probenicid

ticlopidine

topiramate

2C9

amiodarone

fluconazole

fluvastatin

fluvoxamine

isoniazid

lovastatin

paroxetine

phenylbutazone

probenicid

sertraline

sulfamethoxazole

sulfaphenazole

teniposide

trimethoprim

zafirlukast

2D6

amiodarone

buproprion

celecoxib

chlorpromazine

chlorpheniramine

cimetidine

clomipramine

cocaine

doxorubicin

fluoxetine

halofantrine

red-haloperidol

levomepromazine

metoclopramide

methadone

mibefradil

moclobemide

paroxetine

quinidine

ranitidine

ritonavir

sertraline

terbinafine

histamine H1 receptor

antagonists

diphenhydramine

chlorpheniramine

demastine

perphenazine

hydroxyzine

tripelennamine

2E1

diethyl-

dithiocarbamate

disulfiram

3A4,5,7

HIV Antivirals:

delaviridine

indinavir

nelfinavir

ritonavir

saquinavir

amiodarone

NOT

azithromycin

chloramphenicol

cimetidine

ciprofloxacin

clarithromycin

diethyl-

dithiocarbamate

diltiazem

erythromycin

fluconazole

fluvoxamine

gestodene

grapefruit juice

itraconazole

ketoconazole

mifepristone

nefazodone

norfloxacin

norfluoxetine

mibefradil

star fruit

verapamil

Inducers

1A2 2B6

phenobarbital

rifampin

rifampin

2C8 2C19

carbamazepine

norethindrone

NOT pentobarbital

prednisone

rifampin

2C9

rifampin

secobarbital

2D6

dexamethasone

rifampin?

2E1

ethanol

isoniazid

3A4,5,7

HIV Antivirals:

efavirenz

nevirapine

barbiturates

carbamazepine

glucocorticoids

modafinil

phenobarbital

phenytoin

rifampin

St. John's wort

troglitazone

pioglitazone

rifabutin

broccoli

brussel sprouts

char-grilled meat

insulin

methly cholanthrene

modafinil nafcillin?

beta- naphthoflavone

omeprazole

tobacco

Administration Schedule for Antidepressants

Antidepressants

Therapeutic Dose

Range (mg/day)

Initial Suggested Dose Administration Schedule**

Selective Serotonin Reuptake Inhibitors (SSRIs)

1

Citalopram (Celexa)

Fluoxetine (Prozac)

Fluvoxamine (Luvox)

Paroxetine (Paxil)

Sertraline (Zoloft)

10 - 40

10 - 40

50 - 300

10 - 50

50 - 150

20 mg in morning with food (10 mg in

elderly and those with comorbid

panic disorder)

20 mg in morning with food (10 mg in

elderly and those with comorbid

panic disorder)

=100 mg in morning with food (50 mg

in elderly and those with comorbid

panic disorder)

20 mg once daily, usually in morning

with food (10mg in elderly and those

with comorbid panic disorder)

50 mg once daily, usually in morning

with food

Increase in 10 mg increments every 7 days as tolerated. Maintain 20 mg for 4

weeks before dose increase.

Increase in 10 mg increments at intervals of 7 days. Maintain 20 mg for 4-6

weeks before dose increase. If significant side effects occur within 7 days,

lower dose or change medication.

Increase in 50 mg increments every 7 days as tolerated. Maintain 200 mg for

at least 4 weeks before further dose increase.

Increase in 10 mg increments at intervals of approximately 7 days up to a

maximum of 40 mg/day. Maintain 20 mg for 4 weeks before dose increase.

Increase in 50 mg increments at intervals of 7 days as tolerated. Maintain 100

mg for 4 weeks before dose increase.

Newer / Atypical Antidepressants

Buproprion

2

(Wellbutrin

SR)

Mirtazapine (Remeron)

Nefazodone (Serzone)

Venlafaxine

4

(Effexor

XR)

3

150 - 450

15 - 45

200 - 600

75 - 300

100 mg in morning

15 mg at bedtime (7.5 mg in elderly

and those with comorbid panic

disorder)

100 mg twice a day with food

37.5 mg in morning with food

Increase to 100 mg twice/day after 7 days. Then increase to 150 mg twice/day

after 3 weeks and to 150 mg three times daily after 6 weeks.

Increase in 15 mg increments (7.5 mg in elderly) as tolerated. Maintain 30 mg

for 4 weeks before further dose increase.

Increase in 100 mg increments at intervals of 7 days as tolerated. Administer

in divided doses. Maintain 200 mg twice/day for 4 weeks before dose

increase.

Increase to 75 mg in morning after 1 week, 150 mg in the morning after 2

weeks, 225 mg in the morning after 4 weeks, and 300 mg in the morning after

6 weeks.

Increase in 25 mg increments every 7 days as tolerated to full therapeutic

dose over period of several weeks. Once daily dosing at bedtime often

minimizes side effects. Adequate trial considered to be 150 mg/day for at least

4 weeks.

Increase in 25 mg increments every 7 days as tolerated to full therapeutic

dose over period of several weeks. Once daily dosing at bedtime often

minimizes side effects. Adequate trial considered to be 150 mg/day for at least

4 weeks.

Increase in 25 mg increments every 7 days as tolerated to full therapeutic

dose over period of several weeks. Once daily dosing at bedtime often

minimizes side effects. Adequate trial considered to be 150 mg/day for at least

4 weeks.

Increase in 10-25 mg increments every 7 days as tolerated to full therapeutic

dose over period of several weeks. Only TCA with therapeutic window. Dosing

too high may be ineffective. Suggest obtaining serum drug levels

6

after 4

weeks if not effective.

Tricyclic Antidepressants (TCAs)

5

Desipramine

(Norpramin)

75 - 300 50 mg at bedtime (25 mg in elderly)

Doxepin (Sinequan) 75 - 300 50 mg at bedtime (25 mg in elderly)

Imipramine (Tofranil) 75 - 300 50 mg at bedtime

Nortriptyline (Pamelor) 40 - 200 25 mg (10 mg in elderly)

GENERAL NOTES ABOUT PRESCRIBING ANTIDEPRESSANTS

1. Many antidepressants are contraindicated for use in conjunction with monoamine oxidase inhibitors (MAOIs). Consultation with a psychiatrist or

pharmacist is recommended before co-administering MAOIs and other antidepressant medications.

2. Consultation with a psychiatrist is recommended before prescribing antidepressants to pregnant females.

3. CAUTIONARY NOTE REGARDING USE OF ANTIDEPRESSANTS IN PATIENTS WITH PARKINSON'S DISEASE: Treatment of Parkinson's

disease often includes the use of selegiline HCl (Eldepryl), which is a type B monoamine oxidase inhibitor (MAOI). Because the use of many

antidepressants is contraindicated in conjunction with an MAOI as stated above, the discontinuation of Eldepryl in order to use certain

antidepressants may be warranted.

** Doses should be increased as tolerated and as clinically indicated. Many patients will respond at doses below the maximum doses indicated in the

therapeutic dose range.

1

SSRIs are recommended in depressed patients with comorbid panic or obsessive-compulsive disorder.

2

Avoid buproprion in patients at high risk for seizures such as patients with a history of seizures, significant central nervous system lesions, or head trauma.

Also avoid buproprion in depressed patients with significant comorbid anxiety or bulimia.

3

Do not combine nefazodone (Serzone) with other drugs that are extensively metabolized by the P450 3A4 isoenzyme system such as terfenadine,

astemizole and cisapride.

4

Venlafaxine (Effexor XR) can cause increases in blood pressure at higher doses.

5

Tricyclics (TCAs) have lower costs but may have more adverse side effects than SSRIs and other newer antidepressants. TCAs may be contraindicated in

patients with certain physical comorbidities such as recent myocardial infarction, cardiac conduction defects, urinary retention, narrow angle glaucoma,

orthostatic hypotension, renal failure and delirium / acute confusional states. Tertiary amine TCAs such as doxepin (Sinequan), imipramine (Tofranil) and

amitriptyline (Elavil) are not recommended in older adults due to their unfavorable side effect profiles.

6

Target blood level is 50-150 ng/mL.

10. Rost K. The Depression Tool Kit for Primary Care (Prototype).

Physician Antidepressant Fact Sheet

Extended Use of Minor Tranquilizers to Treat Depression Is Contraindicated

(10)

Anxiolytic medications (benzodiazepines and barbiturates) have

not been shown to be effective in treating depression. Anxiolytics may be useful in special cases as an adjunctive medication (not to exceed 12

weeks) for patients with pronounced anxiety. Benzodiazepines may be useful (not to exceed 6 weeks) for pronounced insomnia. Treating Elderly

Patients With Antidepressants (10)

(10)

More sensitive to side effects, particularly to those of tricyclics; start with SSRIs, consider using secondary

amine tricyclics (e.g., nortriptyline, desipramine) if nonresponsive to SSRIs. Are often on multiple other medications (beware of drug interactions).

Metabolism is slower; start with lower doses, increase doses slowly. Discontinuing Antidepressant Therapy

(10)

While antidepressant medications are generally considered safe, they should be discontinued if they are not required. For first episodes of

depression, it may be appropriate to discontinue medication after 4-9 months of continuation phase treatment since only 50% will have another

episode of depression. Tricyclic antidepressants and other drugs listed on the administration schedule should be tapered if the patient has had

exposure at therapeutic dosages for 3 months or more. A tapering schedule of tricyclics over 2 to 4 weeks is recommended.

This Administration Schedule for Antidepressants was taken from the MacArthur Tool Kit, Allan J. Dietrich, MD, Head, MacArthur Initiative Steering

Committee, Dartmouth Medical School.

=Please note per Drug Facts and Comparisons, 2002, Luvox starting dose is 50mg as a single daily bedtime dose. The dose should be increased in

50mg increments every 4-7 days, as tolerated until maximum therapeutic benefit is achieved and not to exceed 300mg/day. Anything greater than

100mg should be in two divided doses.

This chart is intended to be used as an educational tool and should not replace clinical judgement.