Simultaneous Assay of Buprenorphine and Norbuprenorphine by Negative Chemical Ionization Tandem Mass Spectrometry*

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Abstract
A method for the simultaneous measurement of buprenorphine and its N-dealkylated metabolite, norbuprenorphine, in human plasma was developed with negative chemical ionization tandem mass spectrometry. Buprenorphine and norbuprenorphine were extracted from biological fluids by solid-phase extraction. The samples were derivatized with heptafluorobutyric anhydride and measured with negative chemical ionization tandem mass spectrometry. Buprenorphine formed a heptafluorobutyryl derivative and norbuprenorphine formed a bis-heptafluorobutyryl derivative; consequently, the sensitivity of norbuprenorphine was substantially higher than buprenorphine. The limit of quantitation (LOQ) for buprenorphine was 0.20 ng/mL, and the LOQ for norbuprenorphine was 0.03 ng/mL. Daily calibration curves were prepared. Buprenorphine was linear from 0.15 ng/mL to 20 ng/mL, and norbuprenorphine was linear between 0.016 ng/mL and 5 ng/mL. Between-run and within-run precision for buprenorphine at 0.5 ng/mL were 13.8% and 9.8%, respectively. Between-run and within-run precision for norbuprenorphine at 0.5 ng/mL were 23.1% and 17.9%, respectively. The molecular anion for buprenorphine was used as a precursor ion, whereas the [M-197]-was used as a precursor ion for norbuprenorphine in tandem mass spectrometry. Product ion spectra from collision-induced dissociation resulted principally from dissociations of the heptafluorobutyryl group. Monitoring select precursor to product ion reactions and using qualifier ion ratios increased the method's sensitivity and selectivity. The method was applied to samples collected from a patient who received oral and subcutaneous buprenorphine. Buprenorphine plasma concentrations ranged from less than 0.20 ng/m/to 8.7 ng/mL.

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