Population pharmacokinetics of melphalan and glutathione S-transferase polymorphisms in relation to side effects

Clin Pharmacol Ther. 2008 May;83(5):749-57. doi: 10.1038/sj.clpt.6100336. Epub 2007 Oct 3.


Melphalan is associated with severe side effects such as mucositis, diarrhea, and myelosuppression. We investigated how much the individual severity of these side effects is predicted by pharmacokinetics. In addition, we studied glutathione S-transferase GSTM1, GSTT1, and GSTP1 polymorphisms in relation to adverse events. A high interindividual pharmacokinetic variability was observed in 84 patients. There was a linear correlation between creatinine and melphalan clearance (P=0.0004). Patients treated with a dose > or = 70 mg/m(2) had a 23-fold increased risk to develop mucositis (P<0.001) and a 12-fold increased risk to develop diarrhea (P<0.001) compared with lower doses. The GSTP1 codon 105 polymorphism may be relevant for development of mucositis and the GSTT1 deletion may predict diarrhea, but these findings require confirmation. Melphalan-induced side effects were significantly dependent only on dose. Therapeutic drug monitoring or genotyping for GST does not appear to be very helpful in optimizing therapy with melphalan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Alkylating / administration & dosage
  • Antineoplastic Agents, Alkylating / adverse effects
  • Antineoplastic Agents, Alkylating / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Female
  • Genotype
  • Glutathione S-Transferase pi / genetics
  • Glutathione S-Transferase pi / metabolism
  • Glutathione Transferase / genetics*
  • Glutathione Transferase / metabolism*
  • Humans
  • Male
  • Melphalan / administration & dosage
  • Melphalan / adverse effects*
  • Melphalan / pharmacokinetics*
  • Middle Aged
  • Polymorphism, Genetic


  • Antineoplastic Agents, Alkylating
  • glutathione S-transferase T1
  • GSTP1 protein, human
  • Glutathione S-Transferase pi
  • Glutathione Transferase
  • glutathione S-transferase M1
  • Melphalan