Cytochrome P450 Enzymes (CYPs)

CYP3A

There are several subtypes of CYP3A, including 3A4 (most common), 3A5, and 3A7.
Up to 50% of all CYP450 metabolised drugs are substrates of CYP3A.
Inter-individual levels of expression vary at least 10-fold. Genetic polymorphisms contribute to this variation.
CYP3A5 has genetic polymorphism (approximately 10% of people have the enzyme). This can decrease exposure to CYP3A metabolised drugs with low oral bioavailability (e.g. simvastatin and felodipine).
Substrates (listed if CYP3A is 'clinically significant') are subject to drug interactions via inhibition and induction of CYP3A by other drugs (also listed).
Drugs may be metabolised by more than one of the CYP enzymes.
The following lists are not exhaustive.

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

About 30% of all CYP450 metabolised drugs are substrates of CYP2D6.
Genetic polymorphisms have a big effect on CYP2D6 activity:
- Poor metabolisers: 5-10% of Caucasians, 5% of Māori, and 1-2% of Asians/Polynesians.
- Ultra-rapid metabolisers: 25% of North Africans, 5-10% of Mediterraneans, 1% of Caucasians.
Substrates (listed if CYP2D6 is 'clinically significant') are subject to drug interactions via inhibition of CYP2D6 by other drugs (also listed).
Drugs may be metabolised by more than one of the CYP450 enzymes.
The following lists are not exhaustive.

Substrates

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

antidepressants, antipsychotics, anti-arrhythmics, lipophilic beta blockers

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

About 15% of all CYP450 metabolised drugs are substrates of CYP2C8/9.
Genetic polymorphism affects CYP2C8/9 activity:
- Poor metabolisers: 2-10% of Caucasians. Other populations (e.g. Asians, Māori, Polynesians) are minimally affected.
Substrates (listed if CYP2C8/9 is 'clinically significant') are subject to drug interactions via inhibition and induction of CYP2C8/9 by other drugs (also listed).
Drugs may be metabolised by more than one of the CYP450 enzymes.
The following lists are not exhaustive.

Substrates

Main drug classes predominantly metabolised by CYP2C8/9 include:

angiotensin II receptor blockers, sulphonylureas, some non-steroidal anti-inflammatories, coumarin anticoagulant (warfarin)

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

About 5% of all CYP450 metabolised drugs are substrates of CYP2C19.
Genetic polymorphism affects CYP2C19 activity:
- Poor metabolisers: 20% of Asians, 25% of Māori, 13% of Polynesians, and < 5% of Caucasians.
- Ultrarapid metabolisers: 10% of Caucasians
Substrates (listed if CYP2C19 is 'clinically significant') are subject to drug interactions via inhibition and induction of CYP2C19 by other drugs (also listed).
Drugs may be metabolised by more than one of the CYP450 enzymes.
The following lists are not exhaustive.

Substrates

Main drug classes predominantly metabolised by CYP2C19 includes:

proton pump inhibitors

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

Less than 5% of all CYP450 metabolised drugs are substrates of CYP1A2.
CYP1A2 is induced by the hydrocarbons in smoking and cruciferous vegetables.
Common genetic polymorphisms have limited effect on CYP1A2 activity.
Substrates (listed if CYP1A2 is 'clinically significant') are subject to drug interactions via inhibition and induction of CYP1A2 by other drugs (also listed).
Drugs may be metabolised by more than one of the CYP450 enzymes.
The following lists are not exhaustive.

Substrates

Main drug classes predominantly metabolised by CYP1A2 include:

Atypical antipsychotics

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

Topic Code: 102194