L01AA02 - Chlorambucil |
Propably not porphyrinogenic |
PNP |
Rationale
No data supporting CYP-affinity of mother substance or of products. Limited hepatic exposure. No observations of interference with CYP-metabolism of other drugs. Not listed as CYP-inducer or inhibitor. One report of uneventful use in AIP patient.
Chemical description
Chlorambucil is a nitrogen mustard analogue that is insoluble in water and contains alkylating groups common to cyscophosphamide and melphalan.
Bifunctional alkylator through formation of cytotoxic ethylene- immonium radical, which bridges two DNA helix chains giving rise to interference with replication.
Therapeutic characteristics
Chlorambucil is an alkylating agent used to treat chronic lymphatic leucemia and as palliative treatment for malignant lymphoma. Most often used in combination therapy.Given perorally. Common adverse reactions of chlorambucil that can be confused with an acute porphyric attack are Nausea, vomiting, diarrhoea. Side effects as nausea and vomiting may be potentially porphyrinogenic through reduction in caloric intake.
Hepatic exposure
Possibly significant.
Metabolism and pharmakokinetics
Chlorambucil is rapidly and extensively metabolized in the liver, principally to phenylacetic acid mustard, which is pharmacologically active. Phenylacetic acid mustard is formed by β-oxidation of the butyric acid side chain of chlorambucil, apparently via the dehydrogenated intermediate 3,4-dehydrochlorambucil. Chlorambucil and phenylacetic acid mustard apparently undergo spontaneous degradation in vivo, forming monohydroxy and dihydroxy derivatives. No observations of interactions with CYP-metabolism of other drugs. Not listed by Rendic (2002) as CYP-inducer or inhibitor.
Preclinical data
Cochon et al found chlorambucil to be non-porphyrinogenic in chick embryos (Cochon, A.C. et al, 1997).
Published experience
Used uneventfully in 54 year old female AIP patient with non-Hodgkin lymphoma (Davies J.H. et al, 2002).
IPNet drug reports
Uneventful use reported in 1 patient with acute porphyria.
References
- Scientific articles
- Rendic, S. Summary of information on human CYP enzymes: human P450 metabolism. Drug metabolism reviews 2002; 34(1&2), 83-448. PMID 11996015. #4559
- Cochon AC, Aldonatti C et al. Evaluation of the porphyrinogenic risk of antineoplastics. J Appl Toxicol 1997;17(3):171-7. PMID 9250538. #4558
- Davies JH, Whitaker SJ. Chlorambucil and acute intermittent porphyria. Clin Oncol (R Coll Radiol) 2002; 14:491-3. PMID 12512972. #3303
- Drug reference publications
- McEvoy GK, editor. Chlorambucil. The AHFS Drug Information 2008. Bethesda, MD: American Society of Health-System Pharmacists; 2009. Electronic version (Septemeber 2009). #3304
- Sweetman SC, editor. Martindale: The complete drug reference. Chlorambucil. Pharmaceutical Press 2009. #3307
- Summary of Product Characteristics
- Norwegian medicines agency. Summary of Product Characteristics (SPC). Leukeran. #3305
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