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Characterization of the metabolism of fenretinide by human liver microsomes, cytochrome P450 enzymes and UDP‐glucuronosyltransferases
| Content Provider | Scilit |
|---|---|
| Author | Illingworth, Na Boddy, Av Daly, Ak Veal, Gj |
| Copyright Year | 2011 |
| Description | Journal: British Journal of Pharmacology Fenretinide (4-HPR) is a retinoic acid analogue, currently used in clinical trials in oncology. Metabolism of 4-HPR is of particular interest due to production of the active metabolite 4′-oxo 4-HPR and the clinical challenge of obtaining consistent 4-HPR plasma concentrations in patients. Here, we assessed the enzymes involved in various 4-HPR metabolic pathways. Enzymes involved in 4-HPR metabolism were characterized using human liver microsomes (HLM), supersomes over-expressing individual human cytochrome P450s (CYPs), uridine 5′-diphospho-glucoronosyl transferases (UGTs) and CYP2C8 variants expressed in Escherichia coli. Samples were analysed by high-performance liquid chromatography and liquid chromatography/mass spectrometry assays and kinetic parameters for metabolite formation determined. Incubations were also carried out with inhibitors of CYPs and methylation enzymes. HLM were found to predominantly produce 4′-oxo 4-HPR, with an additional polar metabolite, 4′-hydroxy 4-HPR (4′-OH 4-HPR), produced by individual CYPs. CYPs 2C8, 3A4 and 3A5 were found to metabolize 4-HPR, with metabolite formation prevented by inhibitors of CYP3A4 and CYP2C8. Differences in metabolism to 4′-OH 4-HPR were observed with 2C8 variants, CYP2C8*4 exhibited a significantly lower Vmax value compared with *1. Conversely, a significantly higher Vmax value for CYP2C8*4 versus *1 was observed in terms of 4′-oxo formation. In terms of 4-HPR glucuronidation, UGTs 1A1, 1A3 and 1A6 produced the 4-HPR glucuronide metabolite. The enzymes involved in 4-HPR metabolism have been characterized. The CYP2C8 isoform was found to have a significant effect on oxidative metabolism and may be of clinical relevance. |
| Related Links | http://europepmc.org/articles/pmc3042207?pdf=render https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042207/pdf http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2010.01104.x/pdf |
| Ending Page | 999 |
| Page Count | 11 |
| Starting Page | 989 |
| e-ISSN | 14765381 |
| DOI | 10.1111/j.1476-5381.2010.01104.x |
| Journal | British Journal of Pharmacology |
| Issue Number | 4 |
| Volume Number | 162 |
| Language | English |
| Publisher | Wiley-Blackwell |
| Publisher Date | 2011-01-21 |
| Access Restriction | Open |
| Subject Keyword | Journal: British Journal of Pharmacology Udp‐glucuronosyltransferases |
| Content Type | Text |
| Resource Type | Article |
