L01AD02 - Lomustine |
Propably not porphyrinogenic |
PNP |
Rationale
CYP-induction or inhibition are not present in clinical use.
Side effects such as nausea, anorexia and vomiting may be potentially porphyrinogenic through reduction in caloric intake.
Chemical description
Lomustine is a nitrosourea-derivative alkylating agent.
Therapeutic characteristics
Lomustine is an antineoplastic agent used in the treatment of brain tumours and resistant or relapsed Hodgkins disease and other lymphomas. Also used to treat lung cancer, malignant melanoma, and various solid tumours. It is administered orally. Common adverse reactions of lomustine that can be confused with an acute porphyric attack are nausea and vomiting. Side effects such as nausea, anorexia and vomiting may be potentially porphyrinogenic through reduction in caloric intake.
Metabolism and pharmakokinetics
Lomustine is extensively metabolized in the liver partly through CYP3A4-dependent hydroxylations giving rise to alkylation metabolites, and by reductive denitrosation via NADPH-cytochrome P450 reductase. Lomustine is a competative inhibitor of CYP2D6 (Rendic,2002; Le Guellec, 1993) and is listed as an inhibitor of CYP3A4 by Rendic (2002) and Zhou (2007). Lomustine significantly inhibited the biotransformation of vinblastine, a CYP3A4-substrate, in an in-vitro study using human liver microsomes (Zhou-Pan, 1993).Lomustine significantly inhibited vindesine biotransformation (A CYP3A4 substrate) (Zhou, XE, 1993). Human pharmacokinetics not fully elucidated. No interactions with CYP-metabolism of other drugs are reportec that could indicate CYP induction.
References
- Scientific articles
- Rendic, S. Summery of information on human CYP enzymes: human P450 metabolism. Drug metabolism reviews 2002; 34(1&2), 83-448. #1025
- Zhou, S.F., Xue, C.C., et al. Clinically 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. #1027
- Zhou, X-J, Zhou-Pan, X-R, et al. Human liver microsomal cytochrome P450 3A isozymes mediated vindesine biotransformation. Metabolic drug interactions. Biochem Pharmacol 1993; 45(4): 853-61. #1915
- Chang TK, Chen H,et al. 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) modulates rat liver microsomal cyclophosphamide and ifosphamide activation by suppressing cytochrome P450 2C11 messenger RNA levels. Drug Metab Dispos. 1994 Sep-Oct;22(5):673-9. PMID 7835216. #4563
- el-Azhary RA, Ahmed AE. Heme metabolism in liver and spleen of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)-treated rats. Biochem Pharmacol. 1984;33(20):3171-5. PMID 6548384. #1913
- Le Guellec C, Lacarelle B, et al. Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes. Cancer Chemother Pharmacol. 1993;32(6):491-5. PMID 8258200. #4564
- Zhou-Pan XR, Sérée E, et al. Involvement of human liver cytochrome P450 3A in vinblastine metabolism: drug interactions. Cancer Res. 1993 Nov 1;53(21):5121-6. #1916
- Drug reference publications
- DrugBank. Lomustine. Accessed:01.07.10. #1912
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