Examination of 209 Drugs for Inhibition of Cytochrome P450 2C8

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.

Changes in the Pharmacokinetics of Rosiglitazone, a CYP2C8 Substrate, When Co-Administered with Amlodipine in Rats

“…The IC50 value of RGM was 8.3 ± 0.54 μM. The other drugs from a wide variety of had IC 50 values of ＞10 μM, and their IC50 values compared with previously published data (Walsky et al, 2005).…”

“…Hypertension is closely associated with diabetes mellitus, and amlodipine has been commonly prescribed with rosiglitazone. Moreover, it has also been reported that amlodipine is an inhibitor of CYP2C8 (Walsky et al, 2005). Accordingly, the potential exists for a drug interaction between rosiglitazone and amlodipine.…”

“…Therefore, rosiglitazone has the possibility to interact with other commonly used agents. Furthermore, the IC50 values of various drugs (including rosiglitazone) for CYP2C8 were examined in vitro (Walsky et al, 2005), and of these, 11 drugs with an IC50 of 10 μM or more and potential combination with rosiglitazone were found. Because rosiglitazone has an IC 50 value of 10 μM or more (Walsky et al, 2005), it was supposed that drug interactions could occur between rosiglitazone and the other 11 drugs, and that these drugs when co-treated could changes its inhibitory effects on CYP2C8, because all are inhibitors of CYP2C8.…”

CYP2C8 and CYP2C9 polymorphisms in relation to tumour characteristics and early breast cancer related events among 652 breast cancer patients

“…Tamoxifen is a moderate CYP2C8 inhibitor (Walsky et al, 2005), a CYP2C9 substrate (Jin et al, 2005), and significantly inhibits CYP2C9 activity in breast cancer patients (Boruban et al, 2006). CYP2C9 is involved in tamoxifen activation, although neither CYP2C9*2 nor CYP2C9*3, which have lower activity than the wild type, were significantly associated with the levels of the potent tamoxifen metabolite endoxifen in one study (Jin et al, 2005).…”

CYP3A4 Mediates Growth of Estrogen Receptor-positive Breast Cancer Cells in Part by Inducing Nuclear Translocation of Phospho-Stat3 through Biosynthesis of (±)-14,15-Epoxyeicosatrienoic Acid (EET)

“…Although ritonavir inhibits CYP3A5 (K I ϭ 0.12 M) as well as 3A4 (K I ϭ 0.10 M) (36), a potential limitation of ritonavir may be an increase of CYP2C8 epoxygenase activity, suggested by the observed increase in CYP2C8 mRNA when CYP3A4 is silenced. Nonetheless, ritonavir does exhibit modest CYP2C8 inhibitory activity as well (IC 50 ϭ 3 M) (37).…”