Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions.

Article Details

Citation

Backman JT, Filppula AM, Niemi M, Neuvonen PJ

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions.

Pharmacol Rev. 2016 Jan;68(1):168-241. doi: 10.1124/pr.115.011411.

PubMed ID
26721703 [ View in PubMed
]
Abstract

During the last 10-15 years, cytochrome P450 (CYP) 2C8 has emerged as an important drug-metabolizing enzyme. CYP2C8 is highly expressed in human liver and is known to metabolize more than 100 drugs. CYP2C8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the number is increasing. Similarly, many drugs have been identified as CYP2C8 inhibitors or inducers. In vivo, already a small dose of gemfibrozil, i.e., 10% of its therapeutic dose, is a strong, irreversible inhibitor of CYP2C8. Interestingly, recent findings indicate that the acyl-beta-glucuronides of gemfibrozil and clopidogrel cause metabolism-dependent inactivation of CYP2C8, leading to a strong potential for drug interactions. Also several other glucuronide metabolites interact with CYP2C8 as substrates or inhibitors, suggesting that an interplay between CYP2C8 and glucuronides is common. Lack of fully selective and safe probe substrates, inhibitors, and inducers challenges execution and interpretation of drug-drug interaction studies in humans. Apart from drug-drug interactions, some CYP2C8 genetic variants are associated with altered CYP2C8 activity and exhibit significant interethnic frequency differences. Herein, we review the current knowledge on substrates, inhibitors, inducers, and pharmacogenetics of CYP2C8, as well as its role in clinically relevant drug interactions. In addition, implications for selection of CYP2C8 marker and perpetrator drugs to investigate CYP2C8-mediated drug metabolism and interactions in preclinical and clinical studies are discussed.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
AbirateroneCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
AmlodipineCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
AtorvastatinCytochrome P450 2C8ProteinHumans
No
Substrate
Inhibitor
Details
BelinostatCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
BrinzolamideCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
CandesartanCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
Candesartan cilexetilCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
CerivastatinCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Details
CimetidineCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
DabrafenibCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
DeferasiroxCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
DexamethasoneCytochrome P450 2C8ProteinHumans
Unknown
Inducer
Details
Dexamethasone acetateCytochrome P450 2C8ProteinHumans
Unknown
Inducer
Details
EnzalutamideCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Details
ErlotinibCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Details
Estradiol acetateCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
Estradiol benzoateCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
Estradiol dienanthateCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
FenofibrateCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
FluticasoneCytochrome P450 2C8ProteinHumans
No
Inhibitor
Details
Fluticasone furoateCytochrome P450 2C8ProteinHumans
No
Inhibitor
Details
Fluticasone propionateCytochrome P450 2C8ProteinHumans
No
Inhibitor
Details
FluvastatinCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Details
GemfibrozilCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
GenisteinCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
IdelalisibCytochrome P450 2C8ProteinHumans
No
Inhibitor
Details
ImatinibCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
KetoconazoleCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
KetoprofenCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
LenvatinibCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
LevothyroxineCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
LiotrixCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
LoratadineCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Details
Medroxyprogesterone acetateCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
Mefenamic acidCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
Mometasone furoateCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
NilotinibCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Inducer
Details
PhenytoinCytochrome P450 2C8ProteinHumans
No
Substrate
Inducer
Details
PyrimethamineCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
QuinidineCytochrome P450 2C8ProteinHumans
No
Inhibitor
Details
QuinineCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Details
RitonavirCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Inducer
Details
RofecoxibCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
SalmeterolCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
SaquinavirCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
SpironolactoneCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
SulfadiazineCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
TegafurCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
TegaserodCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
TestosteroneCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
Testosterone cypionateCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
Testosterone enanthateCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
Testosterone undecanoateCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
TiclopidineCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
TrametinibCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
TroglitazoneCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Details
TroleandomycinCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
WarfarinCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
Drug Interactions
DrugsInteraction
Almotriptan
Secobarbital
The metabolism of Almotriptan can be increased when combined with Secobarbital.
Almotriptan
Bexarotene
The metabolism of Almotriptan can be decreased when combined with Bexarotene.
Almotriptan
Spironolactone
The metabolism of Almotriptan can be decreased when combined with Spironolactone.
Almotriptan
Loratadine
The metabolism of Almotriptan can be decreased when combined with Loratadine.
Almotriptan
Medroxyprogesterone acetate
The metabolism of Almotriptan can be decreased when combined with Medroxyprogesterone acetate.
Almotriptan
Irbesartan
The metabolism of Almotriptan can be decreased when combined with Irbesartan.
Almotriptan
Fluvastatin
The metabolism of Almotriptan can be decreased when combined with Fluvastatin.
Almotriptan
Pioglitazone
The metabolism of Almotriptan can be decreased when combined with Pioglitazone.
Almotriptan
Genistein
The metabolism of Almotriptan can be decreased when combined with Genistein.
Almotriptan
Topiroxostat
The metabolism of Almotriptan can be decreased when combined with Topiroxostat.
Interactions
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