Determination of plasma fentanyl by GC-mass spectrometry and pharmacokinetic analysis

GC-mass spectrometry was used to measure extremely low levels of fentanyl in dog plasma. Deuterated fentanyl was synthesized for use as an internal standard. Fentanyl was hydrolyzed to despropionyl fentanyl by 20% DCl in in deuterium oxide. Mass spectrometric analysis of the product revealed that the molecular ion was three mass units higher than that of the authentic despropionyl fentanyl, indicating that the deuterium exchange reactions occurred at this stage. Deuterated despropionyl fentanyl was reesterified by propionyl chloride to fentanyl-d3. The drug was assayed in biological fluids by extraction into ethyl acetate followed by analysis with GC-chemical-ionization mass spectrometry. The lowest measurable plasma fentanyl level is 500 pg/ml. The method is highly selective and is suitable for monitoring the time course of plasma drug levels. Evaluation of pharmacokinetic data from experiments using nine dogs revealed a triphasic phenomenon. No measurable amounts of the major metabolites, depropionyl fentanyl and norfentanyl, were detected.