Metabolic dealkylation and hydroxylation reactions in xenobiotics are common and may take place at different sites in the molecules. Sometimes confusion may arise as to the nature and site of the resulting metabolic change when there is more than one potential site. The use of GC-MS in resolving the problem has been demonstrated by using tramadol as example. Human urine samples containing tramadol and its metabolites were extracted under basic pH conditions and analyzed by GC-MS, in the electron impact and chemical ionization modes, before and after trimethylsilyl (TMS) derivatization. By recognizing the mass-to-charge ratios of molecular and base-peak ions in the mass spectra, it was possible to predict and designate sites of demethylation and hydroxylation in tramadol metabolites. In addition to the designation of the known tramadol metabolites, the practice has led to the tentative characterization of hydroxytramadol and norhydroxytramadol as new metabolites of tramadol in humans. Possible extension of the modus operandi to other xenobiotics was discussed.
The two antiparkinsonian drugs procyclidine and benzhexol are presently finding considerable favor for their euphoric hallucinogenic effects among drug abusers in some countries. In anticipation of their possible scheduling in national drug laws, gas chromatography-mass spectrometry (GC-MS) methods for their detection in urine will be required. However, because of uncertainty of the metabolic fate of the two drugs in humans, the urinary target analytes for GC-MS detection were not well defined. The problem was addressed in the present study in which it was found that mono-hydroxy metabolites, where hydroxylation took place at the cyclohexane ring in both drugs, could be endorsed as the major target analytes. The metabolites could only be detected as the mono- and/or di-trimethylsilyl (TMS) derivatives. The predominance of either derivative depended on the temperature and time of heating with the derivatizing reagent. Because of the basic properties of the hydroxy metabolites, analytic method optimization was needed for their detection in urine included extraction under basic pH conditions. Urine hydrolysis with β-glucuronidase did not have an effect on the recovery of the metabolites, but was usually performed in search for other drugs. Because of the relative abundance of ions, the electron impact mass spectra of the mono-TMS derivatives and the chemical ionization (CI) mass spectra of the mono- and di-TMS derivatives of the hydroxy metabolites of both drugs were found to be more structurally informative. The CI mass spectra of the di- TMS derivatives have the additive advantage of being potentially useful for quantitative analysis.
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