Delineation of the interactions between the chemotherapeutic agent eribulin mesylate (E7389) and human CYP3A4.
OBJECTIVE
Eribulin mesylate (E7389), a structurally simplified, synthetic analog of the marine natural product halichondrin B, acts by inhibiting microtubule dynamics via mechanisms distinct from those of other tubulin-targeted agents. Eribulin is currently in Phase III clinical trials for the treatment of metastatic breast cancer. Since drug-induced modulation of cytochrome P450 enzymes, particularly CYP3A4, is a frequent cause of drug-drug interactions, we examined the effects of eribulin on the activity and expression of hepatic and recombinant CYP3A4 (rCYP3A4) in vitro.


METHODS
Identification of the enzyme(s) responsible for eribulin metabolism was based on compound depletion and metabolite formation in reaction mixtures containing subcellular liver fractions or primary human hepatocytes, plus recombinant Phases I and II metabolic enzymes. The role of the enzyme(s) identified was confirmed using enzyme-selective inhibitors and the correlation with prototypic enzyme activity. The effect of eribulin on enzymatic activity was characterized using both microsomal preparations and recombinant enzymes, while the possible modulation of protein expression was evaluated in primary cultures of human hepatocytes.


RESULTS
Eribulin was primarily metabolized by CYP3A4, resulting in the formation of at least four monooxygenated metabolites. In human liver microsomal preparations, eribulin suppressed the activities of CYP3A4-mediated testosterone and midazolam hydroxylation with an apparent K (i) of approximately 20 microM. Eribulin competitively inhibited the testosterone 6beta-hydroxylation, nifedipine dehydration, and R-warfarin 10-hydroxylation activities of rCYP3A4, with an average apparent K (i) of approximately 10 microM. These inhibitions were reversible, with no apparent mechanism-based inactivation. Eribulin did not induce the expression or activities of CYP1A and CYP3A enzymes in human primary hepatocytes, and clinically relevant concentrations of eribulin did not inhibit CYP3A4-mediated metabolism of various therapeutic agents, including carbamazepine, diazepam, paclitaxel, midazolam, tamoxifen, or terfenadine.


CONCLUSIONS
Eribulin was predominantly metabolized by CYP3A4. Although eribulin competitively inhibited the testosterone 6beta-hydroxylation, nifedipine dehydration, and R-warfarin 10-hydroxylation activities of rCYP3A4, it did not induce or inhibit hepatic CYP3A4 activity at clinically relevant concentrations. As eribulin does not appear to affect the metabolism of other therapeutic agents by CYP3A4, our data suggest that eribulin would not be expected to inhibit the metabolism of concurrently administered drugs that are metabolized by CYP3A4, suggesting a minimal risk of drug-drug interactions in the clinical setting.
Zhang
Z-Y
ZY
Department of Drug Disposition, Eisai Research Institute, 4 Corporate Drive, Andover, MA 01810, USA. zhi-yi_zhang@eri.eisai.com
King
B M
BM
Pelletier
R D
RD
Wong
Y N
YN
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005663:Furans / Q000378:metabolism / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007231:Infant, Newborn; D007659:Ketones / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009543:Nifedipine / Q000378:metabolism; D011994:Recombinant Proteins; D013739:Testosterone / Q000378:metabolism; D014859:Warfarin / Q000378:metabolism; D000095662:Polyether Polyketides
D000970:Antineoplastic Agents; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D005663:Furans; D007659:Ketones; D009543:Nifedipine; D011994:Recombinant Proteins; D013739:Testosterone; D014859:Warfarin; C510163:CYP3A4 protein, human; C490954:eribulin; D000095662:Polyether Polyketides