Busulfan Kabi Mechanism of Action

Pharmacology: Pharmacodynamics: Busulfan is a bifunctional alkylating agent in which two labile methanesulfonate groups are attached to opposite ends of a four-carbon alkyl chain. In aqueous media, busulfan hydrolyzes to release the methanesulfonate groups. This produces reactive carbonium ions that can alkylate DNA. DNA damage is thought to be responsible for much of the cytotoxicity of busulfan.
Pharmacokinetics: The pharmacokinetics of busulfan was studied in 59 patients participating in a prospective trial of a busulfan-cyclophosphamide preparatory regimen prior to allogeneic hematopoietic progenitor stem cell transplantation. Patients received 0.8 mg/kg busulfan every six hours, for a total of 16 doses over four days. Fifty-five of fifty-nine patients (93%) administered busulfan maintained AUC values below the target value (<1500 µM·min). (See Table 1.)

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Busulfan pharmacokinetics showed consistency between dose 9 and dose 13 as demonstrated by reproducibility of steady state C_max and a low coefficient of variation for this parameter.
Distribution: Busulfan achieves concentrations in the cerebrospinal fluid approximately equal to those in plasma. Busulfan primarily binds to albumin (Mean ± standard deviation=32.4 ± 2.2%).
Metabolism: Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. This conjugate undergoes extensive oxidative metabolism in the liver.
Excretion: Following administration of ¹⁴C-labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces.
Specific Populations: Pediatric Patients: In a pharmacokinetic study of busulfan in 24 pediatric patients, the population pharmacokinetic (PPK) estimates of busulfan for clearance (CL) and volume of distribution (V) were determined. For actual body weight, PPK estimates of CL and V were 4.04 L/hr/20 kg (3.37 ml/min/kg; interpatient variability 23%); and 12.8 L/20 kg (0.64 L/kg; interpatient variability 11%).