In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity.
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Monbaliu J, Gonzalez M, Bernard A, Jiao J, Sensenhauser C, Snoeys J, Stieltjes H, Wynant I, Smit JW, Chien C
In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity.
Drug Metab Dispos. 2016 Oct;44(10):1682-91. doi: 10.1124/dmd.116.070672. Epub 2016 Aug 8.
- PubMed ID
- 27504016 [ View in PubMed]
- Abstract
Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and abiraterone and its major metabolites, abiraterone sulfate and abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC50 values: 1.3-3.0 microM, 1.6-2.9 microM, 0.044-0.15 microM, and 5.4-5.9 microM, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted comprising 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again 1 hour after the administration of abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and abiraterone were determined for up to 72 hours after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 125 [90% confidence interval (CI), 99.9-156] for Cmax and 146 (90% CI, 126-171) for AUClast Exposure to M-III and M-IV was reduced by 10% to 13%. Plasma abiraterone concentrations were consistent with previous studies. These results show that abiraterone only weakly inhibits CYP2C8 in vivo.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Abiraterone Cytochrome P450 2C8 Protein Humans UnknownInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAmiodaroneAbiraterone The metabolism of Amiodarone can be decreased when combined with Abiraterone. BrigatinibAbiraterone The metabolism of Brigatinib can be decreased when combined with Abiraterone. FluorouracilAbiraterone The metabolism of Fluorouracil can be decreased when combined with Abiraterone. PaclitaxelAbiraterone The metabolism of Paclitaxel can be decreased when combined with Abiraterone. PazopanibAbiraterone The metabolism of Pazopanib can be decreased when combined with Abiraterone.