The effect of metronidazole on busulfan pharmacokinetics in patients undergoing hematopoietic stem cell transplantation

Busulfan (Bu) is an important component of some myeloablative regimens prior to stem cell transplantation (SCT). Over the last few years it has been shown that other drugs administered concomitantly can influence Bu pharmacokinetics. In the present study, we compared Bill concentrations (trough levels) in three groups of patients. Group A (n = 5) received metronidazole as graft-versus-host disease prophylaxis during Bu treatment. Group B (n = 9) received Bu only for 2 days followed by 2 days of Bu and metronidazole. Group C (n = 10) was a control group that received Bu without metronidazole. The mean Bu levels for Group A receiving metronidazole during conditioning was significantly (P < 0.001) higher (948 +/- 280 ng/ml), compared to those observed in the control group (507 +/- 75 ng/ml). In Group B, the administration of metronidazole resulted in a significant (P < 0.001) increase in Bu levels (807 +/- 90 ng/ml) during the last 2 days, compared to 452 +/- 68 ng/ml during the first 2 days. In Group A, one patient died with multiorgan failure, three experienced veno-occlusive disease (VOD) and one developed hemorrhagic cystitis. Elevated liver transaminases (AST, ALT) and bilirubin were detected in all Group A patients. In Group B, six patients had elevated liver function tests but no VOD was observed. We conclude that metronidazole should not be administered simultaneously with Bu to avoid the high plasma levels of Bu, which may lead to severe toxicity and/or treatment related mortality.