Canterbury DHB

Context

Cytochrome P450 Enzymes (CYPs)

CYP3A

Substrates

Gastrointestinal System

 

 

domperidone, loperamide

Cardiovascular System

 

amiodarone, amlodipine, apixaban, atorvastatin, bezafibrate, diltiazem, doxazosin, felodipine, nifedipine, propranolol, quinine, rivaroxaban, simvastatin, sildenafil, tadalafil, ticagrelor, vardenafil, verapamil

Respiratory System

 

chlorpheniramine, loratadine

Central Nervous System

 

alprazolam, aprepitant, aripiprazole, buspirone, carbamazepine, clonazepam, cocaine, diazepam, fentanyl, galantamine, haloperidol, methadone, midazolam, pimozide, quetiapine, risperidone, triazolam, ziprasidone

Infections

 

boceprevir, clarithromycin, dapsone, erythromycin, indinavir, itraconazole, ketoconazole, nelfinavir, nevirapine, ritonavir, roxithromycin, saquinavir, telapravir, voriconazole

Endocrine System

 

dexamethasone, finasteride, fludrocortisone, methylprednisolone, oestradiol, progesterone, testosterone

Malignant Disease and Immunosuppression

 

ciclosporin, docetaxel, everolimus, flutamide, imatinib, irinotecan, paclitaxel, sirolimus, sorafenib, tacrolimus, vinblastine, vincristine

Anaesthesia

lignocaine

Inhibitors (may cause an increase in plasma concentrations of substrates)

NB Weak inhibitors are not included and are expected to have minimal clinical effect.

Strong

≥ five-fold increase in concentrations (AUC) or ≥ 80% decrease in clearance of in vivo CYP probe

Moderate

≥ two-fold but < five-fold concentrations (AUC) increase or ≥ 50% but < 80% decrease in clearance of in vivo CYP probe

aprepitant

azatanavir

boceprevir

ciclosporin

clarithromycin

ciprofloxacin

erythromycin

diltiazem

grapefruit juice

fluconazole

indinavir

imatinib*

itraconazole

montelukast

ketoconazole

saquinavir

nelfinavir

verapamil

ritonavir

 

telapravir

 

voriconazole

 

*Other tyrosine kinase inhibitors e.g. erlotinib may be strong inhibitors of CYP3A but evidence is currently lower level

Inducers (may cause a decrease in plasma concentrations of substrates)

Significant

≥ two-fold decrease in concentrations (AUC) or ≥ 100% increase in clearance of n vivo CYP probe

bosentan

modafinil

rifampicin

carbamazepine

phenytoin

St John’s wort

efavirenz

 

 

CYP2D6

Substrates

Main drug classes predominantly metabolised by CYP2D6 are lipophilic bases including:

Main Drugs

amitriptyline

doxepin

mexiletine

risperidone^

aripiprazole^

flecainide

mianserin

sertraline

atomoxetine

fluoxetine

nortriptyline

tamoxifen*

carvedilol

haloperidol

ondansetron

timolol

chlorpheniramine

imipramine

paroxetine

tolterodine

chlorpromazine

lidocaine

perhexiline

tramadol

clomipramine

maprotiline

procainamide

trimipramine

clonidine

MDMA ("ecstasy")

promethazine

tropisetron

codeine*

metoclopramide

propafenone

venlafaxine

desipramine

metoprolol

propranolol

zuclopenthixol

dextromethorphan

 

 

 

* prodrug - metabolised to active drug by 2D6

^ metabolised by this enzyme but changes in CYP2D6 have modest clinical effects

Inhibitors (may cause an increase in plasma concentrations of substrates)

NB Weak inhibitors are not included and are expected to have minimal clinical effect.

Strong

≥ five-fold increase in concentrations (AUC) or ≥ 80% decrease in clearance of in vivo CYP probe

Moderate

≥ two-fold but < five-fold concentrations (AUC) increase or ≥ 50% but < 80% decrease in clearance of in vivo CYP probe

bupropion

chlorpheniramine

fluoxetine (norfluoxetine)

chlorpromazine

paroxetine

cinacalcet

perhexiline

cocaine

 

dextropropoxyphene

 

flecainide

 

haloperidol

 

levomepromazine

 

MDMA ("ecstasy")

 

moclobemide

 

quinine

 

terbinafine

Inducers

CYP2D6 is not subject to enzyme induction by other drugs.

CYP2C8/9

Substrates

Main drug classes predominantly metabolised by CYP2C8/9 include:

Main Drugs

candesartan

glipizide

naproxen

tenoxicam

celecoxib

ibuprofen

phenytoin

warfarin

glibenclamide

irbesartan

piroxicam

 

gliclazide

losartan*

rosiglitazone

 

glimepiride

meloxicam

sulfamethoxazole

 

*losartan is metabolised by 2C8/9 to active metabolite (E-3174) (15% converted), which is more active than the parent has a longer half-life and has an fe = 0.

Inhibitors (may cause an increase in plasma concentrations of substrates)

NB Weak inhibitors are not included and are expected to have minimal clinical effect.

Strong

≥ five-fold increase in concentrations (AUC) or ≥ 80% decrease in clearance of in vivo CYP probe

Moderate

≥ two-fold but < five-fold concentrations (AUC) increase or ≥ 50% but < 80% decrease in clearance of in vivo CYP probe

fluconazole

 

amiodarone

 

 

 

isoniazid

 

 

 

ketoconazole

 

 

 

ritonavir

 

 

 

voriconazole

 

Inducers (may cause a decrease in plasma concentrations of substrates)

Significant

≥ two-fold decrease in concentrations (AUC) or ≥ 100% increase in clearance of n vivo CYP probe

phenobarbital

phenytoin

primidone

rifampicin

CYP2C19

Substrates

Main drug classes predominantly metabolised by CYP2C19 includes:

Main Drugs

clopidogrel*

indometacin

moclobemide

pantoprazole

cyclophosphamide*

isoniazid

nelfinavir

proguanil

diazepam

lansoprazole

omeprazole

selegiline

imipramine

 

 

 

* prodrug - metabolised to active drug by 2C19

Inhibitors (may cause an increase in plasma concentrations of substrates)

NB Weak inhibitors are not included and are expected to have minimal clinical effect.

Strong

≥ five-fold increase in concentrations (AUC) or ≥ 80% decrease in clearance of in vivo CYP probe

Moderate

≥ two-fold but < five-fold concentrations (AUC) increase or ≥ 50% but < 80% decrease in clearance of in vivo CYP probe

fluconazole

 

clarithromycin

 

fluvoxamine

 

fluoxetine (norfluoxetine)

 

 

 

indometacin

 

 

 

ketoconazole

 

 

 

lansoprazole

 

 

 

moclobemide

 

 

 

omeprazole

 

 

 

pantoprazole

 

 

 

tranylcypromine

 

Inducers (may cause a decrease in plasma concentrations of substrates)

Significant

≥ two-fold decrease in concentrations (AUC) or ≥ 100% increase in clearance of n vivo CYP probe

carbamazepine

rifampicin

ritonavir

St John’s wort

phenytoin

 

 

 

CYP1A2

Substrates

Main drug classes predominantly metabolised by CYP1A2 include:

Main Drugs

caffeine

flutamide

riluzole

ropivacaine

clomipramine

olanzapine

ropinirole

theophylline

clozapine

 

 

 

Inhibitors (may cause an increase in plasma concentrations of substrates)

NB Weak inhibitors are not included and are expected to have minimal clinical effect.

Strong

≥ five-fold increase in concentrations (AUC) or ≥ 80% decrease in clearance of in vivo CYP probe

Moderate

≥ two-fold but < five-fold concentrations (AUC) increase or ≥ 50% but < 80% decrease in clearance of in vivo CYP probe

ciprofloxacin

 

amiodarone

 

 

 

ethinylestradiol

 

 

 

fluvoxamine

 

 

 

interferon

 

 

 

ketoconazole

 

 

 

quinolones

 

Inducers (may cause a decrease in plasma concentrations of substrates)

Significant

≥ two-fold decrease in concentrations (AUC) or ≥ 100% increase in clearance of n vivo CYP probe

Induced by food and environmental factors (e.g. charred/barbecued food, smoking).

charred/

barbecued foods

phenobarbital

primidone

smoking

cruciferous vegetables

(e.g. broccoli)

phenytoin

rifampicin

 

Information about this Canterbury DHB document (102194):

Document Owner:

Not assigned (see Who's Who)

Last Updated:

May 2019 (Drug Metabolism and Transport)

Next Review Due:

May 2023

Keywords:

Note: Only the electronic version is controlled. Once printed, this is no longer a controlled document.

Topic Code: 102194