Examination of 209 drugs for inhibition of cytochrome P450 2C8.

Article Details

Citation

Walsky RL, Gaman EA, Obach RS

Examination of 209 drugs for inhibition of cytochrome P450 2C8.

J Clin Pharmacol. 2005 Jan;45(1):68-78.

PubMed ID
15601807 [ View in PubMed
]
Abstract

Cytochrome P450 2C8 is involved in the metabolism of drugs such as paclitaxel, repaglinide, rosiglitazone, and cerivastatin, among others. An in vitro assessment of 209 frequently prescribed drugs and related xenobiotics was carried out to examine their potential to inhibit CYP2C8. A validated sensitive, moderate-throughput high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) assay was used to detect N-desethylamodiaquine, the CYP2C8-derived major metabolite of amodiaquine metabolism, using heterologously expressed recombinant CYP2C8 (rhCYP2C8) and pooled human liver microsomes. The 209 drugs were first tested at 30 muM for their ability to inhibit rhCYP2C8. Forty-eight compounds exhibited greater than 50% inhibition and were further evaluated for measurement of IC50. The six most potent inhibitors (IC50 <1 microM) from this set were measured for IC50 in pooled human liver microsomes, and the most potent inhibitor identified was the leukotriene receptor antagonist, montelukast (IC50 = 19.6 nM). Inhibitors of CYP2C8 were identified from a wide variety of therapeutic classes, with no single class predominating. Other potent inhibitors included candesartan cilexetil (cyclohexylcarbonate ester prodrug of candesartan), zafirlukast, clotrimazole, felodipine, and mometasone furoate. Seventeen moderate inhibitors of rhCYP2C8 (1 < IC50 < 10 microM) included salmeterol, raloxifene, fenofibrate, ritonavir, levothyroxine, tamoxifen, loratadine, quercetin, oxybutynin, medroxyprogesterone, simvastatin, ketoconazole, ethinyl estradiol, spironolactone, lovastatin, nifedipine, and irbesartan. These in vitro data were used along with clinical pharmacokinetic information in predicting potential drug-drug interactions that could occur by inhibition of CYP2C8. Although almost all drugs tested are not expected to cause drug interactions via inhibition of CYP2C8, montelukast was identified as being of concern as a potential inhibitor of clinical relevance. These findings are discussed in context to potential drug interactions that could be observed between these agents and drugs for which CYP2C8 is involved in metabolism and warrant investigation of the possibility of clinical drug interactions mediated by inhibition of this enzyme.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
CandesartanCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
Candesartan cilexetilCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
ClotrimazoleCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
EthinylestradiolCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Details
FelodipineCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
FenofibrateCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
IrbesartanCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Details
KetoconazoleCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
LevothyroxineCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
LiotrixCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
LoratadineCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Details
LovastatinCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
Medroxyprogesterone acetateCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
MometasoneCytochrome P450 2C8ProteinHumans
No
Inhibitor
Details
Mometasone furoateCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
MontelukastCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Details
NifedipineCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
OxybutyninCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
QuercetinCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
RaloxifeneCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
RitonavirCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Inducer
Details
SalmeterolCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
SimvastatinCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Details
SpironolactoneCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
TamoxifenCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
ZafirlukastCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Details
Drug Interactions
DrugsInteraction
Interactions
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