L01DB01 - Doxorubicin |
Propably not porphyrinogenic |
PNP |
Rationale
Substrate and weak inhibitor of CYP3A4, but no indications of CYP-inducing capacity. Side effects such as nausea and vomiting may be potentially porphyrinogenic through reduction in caloric intake.
Chemical description
Doxorubicin is an anthracycline antineoplastic antibiotic isolated from a Steptomyces peucetius strain.
Therapeutic characteristics
Doxorubicin has a wide therapeutic range and is used in the treatment of e.g. breast cancer, lung cancer, sarcoma, maligant lymphoma, and acute leuecamias. Often used in combination with other antineoplasics. Administered as an intravenous infusion. Common adverse reactions of doxorubicin that can be confused with an acute porphyric attack are vomiting and nausea. It may also colour the ruin red. Side effects such as nausea and vomiting may be potentially porphyrinogenic through reduction in caloric intake.
Metabolism and pharmacokinetics
Doxorubicin is meabolised in the liver from quinone to the highly cytotoxic semiquinone by NADPH cytochrome P450 reductase. Listed as an inhibitor and substrate of CYP 3A4 by Rendic (2002). Baumhäkel et al (2001) found that doxorubicinhad only a minor inhibitory effect on human CYP 3A4. Doxorubicin does not activate PXR (Sinz, 2006; Harmsen, 2009). No interactions described pointing to interference with CYP-metabolism of other drugs. Not listed as CYP-inducer.
Published experience
Used uneventfully by 2 PV women suffering from breast cancer (Thiery-Vuillemin, 2008). Used uneventfully by 1 AIP women suffering from acute myelogenous leukemia (Wehmeier, 1987). Used uneventfully in 16-year old PV girl suffering from acute lymphoblastic leukemia. (Samuels, 1984). Used uneventfully in PV woman suffering from breast cancer (Scarlett, 1995).
IPNet drug reports
Uneventful use reported in 2 patients with acute porphyria.
References
- Scientific articles
- 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(1):35-43. PMID 18839173. #4573
- Samuels B, Bezwoda WR, et al. Chemotherapy in porphyria. S Afr Med J. 1984;65(23):924-6. #1924
- Scarlett JD, Corry J, Jeal PN. Cytotoxic chemotherapy and radiotherapy in a patient with breast cancer and variegate porphyria (VP). Aust N Z J Med. 1995;25(6):742-3. #2001
- Sinz M, Kim S, et al. Evaluation of 170 xenobiotics as transactivators of human pregnane X receptor (hPXR) and correlation to known CYP3A4 drug interactions. Curr Drug Metab. 2006;7(4):375-88. PMID 16724927. #4577
- Thiery-Vuillemin A, Chaigneau L, et al. Anticancer therapy in patients with porphyrias: evidence today. Expert Opin Drug Saf. 2008;7(2):159-65. PMID 18324878. #4578
- Wehmeier A, Fischer JT, et al. Polychemotherapy of acute myelogenous leukemia in a patient with acute intermittent porphyria. Klin Wochenschr. 1987;65(7):338-40. #1936
- Drug reference publications
- McEvoy GK, editor. Doxorubicin. The AHFS Drug Information 2008. Bethesda, MD: American Society of Health-System Pharmacists; 2009. Electronic version (04.05.10). #1999
- Sweetman SC, editor. Martindale: The complete drug reference. Doxorubicin. Pharmaceutical Press 2009. #2003
- Summary of Product Characteristics
- Norwegian medicines agency. Summary of Product Characteristics (SPC). Adriamycin. #2000
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