L01CB01 - Etoposide |
Propably not porphyrinogenic |
PNP |
Rationale
Etoposide is a ligand and weak inhibitor of Cyp3A4. In spite of a molecular structure compatible with a potential for irreversible CYP-inhibition, theoretical and clinical evidence point to no significant CYP-inducing capacity. Side effects such as nausea and vomiting may be potentially porphyrinogenic through reduction in caloric intake.
Chemical description
Etoposide is a semisyntetic derivative of podophyllotoxin. The central tetracyclic structure carries a benzodioxole function with theoretical potential for generation of reactive carbamene, which strongly coordinates to the CYP iron atom (Fontana, 2005).
Therapeutic characteristics
Etoposide is used alone or in combination therapy to treat lung cancer, acute non-lymphatic anemia, non-Hodgkin lymphoma, Mb Hodgkin, and testicular cancer. Administered by venous infusion, but may also be given orally. Common adverse reactions of etoposide that can be confused with an acute porphyric attack nausea, vomiting, and diarrhoea. Less common are abdominal pain and peripheral neuropathies of limited severity. Side effects such as nausea and vomiting may be potentially porphyrinogenic through reduction in caloric intake.
Metabolism and pharmakokinetics
Metabolized in the liver by CYP 3A4 and to lesser extent by CYP 1A2 and 2E1 (Kawashiro, 1998). Molecular structure with potential for irreversible Cyp-inhibition, but findings differ: Rendic (2002) and Zhou (2007) report etoposide to be a weak inhibitor of 3A4, while Baumhakel (2001) found no clear inhibitory effect in human liver microsomes. Found to be a ligand to PXR in studies with mice (Schuetz, 2002) but not in human PXR (Sinz, 2006; Harmsen, 2009). No interactions with CYP-metabolism of other drugs are observed.
IPNet drug reports
No.
References
- Scientific articles
- Fontana, E, Dansette, PM, et al. Cytochrome P 450 enzymes mechanism based inhibitors: Common sub-structures and reactivity. Curr Drug Metabol 2005; 6:413-54. #1359
- Harmsen, S, Meijerman, I, et al. Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor. Cancer Chemother Pharmacol 2009; 64:35â-43. #1972
- Kawashiro, T, Yamashita, K, et al. A study of the metabolism of etoposide and possible interactions with antitumor or supporting agents by human liver microsomes. JPET 1998; 286:1294â-1300. #3349
- Rendic, S. Summery of information on human CYP enzymes: human P450 metabolism. Drug metabolism reviews 2002; 34(1&2), 83-448. #1025
- Scheutz, E, Lan, L, et al. Development of a real-time in vivo transcription assay; application reveals pregane X-receptor mediated induction of CYP 3A4 by cancer chenotherapeutic agents. Mol Pharmacol 2002; 62:439â-445. #1974
- Sinz, M, Kim, S, et al. Evaluation of 170 xenobiotics as transactivators of hPXR and correaltion to CYP 3A4 drug interactions. Curr Drug metabol 2006; 7:375-388. #1363
- Zhou, S.F., Xue, C.C., et al. Clinicallay important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit 2007; 29(6):687:710." #3351
- Drug reference publications
- Sweetman SC, editor. Martindale: The complete drug reference. Etoposide. Pharmaceutical Press 2009. #1975
- Summary of Product Characteristics
- Norwegian medicines agency. Summary of Product Characteristics (SPC). Eposin. #3350
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