title: Busulfan and metronidazole: an often forgotten but significant drug interaction.
abstract: OBJECTIVE
  To report the case of a clinically significant drug interaction between intravenous busulfan and oral metronidazole observed through busulfan therapeutic drug monitoring (TDM).
  
  
  METHODS
  A 7-year-old boy with a history of myelodysplasia that progressed to acute myeloid leukemia received busulfan with therapeutic drug monitoring (TDM), clofarabine, and thiotepa as a pretransplant conditioning regimen for a cord blood transplant. The patient received metronidazole the day after a busulfan test dose of 0.5 mg/kg was administered. On the day of the first busulfan therapeutic dose, TDM was performed and the clearance of busulfan was significantly decreased by 46%. After 2 doses of busulfan therapy, the course area under the curve was exceeded, requiring discontinuation of busulfan. Metronidazole is not known to affect glutathione or the glutathione S-transferase A1 (GSTA1) enzyme system or cytochrome P450 (CYP) 3A4.
  
  
  CONCLUSIONS
  Busulfan is a bifunctional alkylating agent widely used in pretransplant conditioning regimens in patients undergoing stem cell transplantation for hematologic malignancies. Busulfan metabolism is best described by hepatic conjugation to glutathione by GSTA1, although some CYP-dependent pathways have been described. Currently there is 1 publication describing the drug interaction between oral busulfan and oral metronidazole, in which concomitant use of metronidazole resulted in higher busulfan trough concentrations and higher risk of veno-occlusive disease. Our case represents a possible drug interaction based on the Horn Drug Interaction Probability Scale.
  
  
  CONCLUSIONS
  Though the mechanistic basis for this interaction is unknown, the risks and benefits of using metronidazole during and in close proximity to busulfan should be carefully considered and therapeutic alternatives to metronidazole should be used when appropriate.
authors: Division of Pharmacy, MD Anderson Cancer Center, Houston, TX, USA. amassaro@mdanderson.org
authors: Alison M
authors: AM
authors: Gulbis
authors: Kirk S
authors: KS
authors: Culotta
authors: Roy B
authors: RB
authors: Jones
authors: Borje S
authors: BS
authors: Andersson
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D002066:Busulfan / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D016360:Clostridioides difficile / Q000302:isolation & purification; D004347:Drug Interactions; D016903:Drug Monitoring; D004761:Enterocolitis, Pseudomembranous / Q000150:complications / Q000188:drug therapy; D006207:Half-Life; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000150:complications / Q000628:therapy*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008795:Metronidazole / Q000009:adverse effects* / Q000627:therapeutic use; D019653:Myeloablative Agonists / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D019172:Transplantation Conditioning / Q000009:adverse effects
chemical_list: D000900:Anti-Bacterial Agents; D018906:Antineoplastic Agents, Alkylating; D019653:Myeloablative Agonists; D008795:Metronidazole; D002066:Busulfan