Gas-chromatographic analysis of busulfan for therapeutic drug monitoring.
The development and validation of a gas chromatographic assay method for determination of total and free busulfan concentrations in human plasma for pharmacokinetic studies is reported. 1,6-Bis(methanesulfonyloxy)hexane, the internal standard, and a potential metabolite, 3-hydroxysulfolane, were synthesized. Plasma and plasma ultrafiltrate samples containing busulfan and internal standard were extracted with ethyl acetate and derivatized with 2,3,5,6-tetrafluorothiophenol prior to gas chromatographic determination. The 63Ni electron-capture detector provided a limit of detection of 0.0600 microgram/ml with a limit of quantitation of 0.100 microgram/ml busulfan in biological samples. Calibration curves were linear from 0.100 to 3.00 micrograms/ml in plasma (500 microliters) and 0.100 to 2.00 micrograms/ml in plasma ultrafiltrate (100 microliters). Extraction and derivatization yields ranged from 78.4% to 89.6% and 56.0% to 71.3%, respectively. Specificity of this assay for busulfan in the presence of its potential metabolites was demonstrated. Also, plasma samples containing co-administered drugs gave no response under these conditions. Clinical samples obtained following administration of a 1 mg/kg oral busulfan dose demonstrate the applicability of this method to analysis of total and free plasma concentrations.
Embree
L
L
Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, Canada.
Burns
R B
RB
Heggie
J R
JR
Phillips
G L
GL
Reece
D E
DE
Spinelli
J J
JJ
Hartley
D O
DO
Hudon
N J
NJ
Goldie
J H
JH
D002066:Busulfan / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood*; D002138:Calibration; D002849:Chromatography, Gas; D016903:Drug Monitoring; D006801:Humans; D010636:Phenols; D012015:Reference Standards; D012044:Regression Analysis; D012680:Sensitivity and Specificity; D013438:Sulfhydryl Compounds
D010636:Phenols; D013438:Sulfhydryl Compounds; C081141:2,3,5,6-tetrafluorobenzenethiol; D002066:Busulfan