Gas chromatographic-mass spectrometric differentiation of atenolol, metoprolol, propranolol, and an interfering metabolite product of metoprolol.

摘要

Over a 10-year period, 1993-2002, Federal Aviation Administration identified 50 pilot fatalities involving atenolol, metoprolol, and propranolol, which is consistent with the fact that these drugs have been in the lists of the top 200 drugs prescribed in the U.S. In a few of the 50 pilot fatality cases, initial analysis suggested the presence of atenolol and metoprolol. However, there was no medical history with these cases supporting the use of both drugs. Therefore, atenolol, metoprolol, and/or propranolol, with their possible metabolite(s), were re-extracted from the selected case specimens, derivatized with pentafluoropropionic anhydride (PFPA), and analyzed by gas chromatography-mass spectrometry (GC-MS). The MS spectra of these three antihypertensives and a metoprolol metabolite are nearly identical. All of the PFPA derivatives had baseline GC separation, with the exception of a metoprolol metabolite product, which co-eluted with atenolol. There were four primary mass fragments (m/z 408, 366, 202, and 176) found with all of the PFPA-beta-blockers and with the interfering metabolite product. However, atenolol has three unique fragments (m/z 244, 172, and 132), metoprolol has two unique fragments (m/z 559 and 107), propranolol has four unique fragments (m/z 551, 183, 144, and 127), and the metoprolol metabolite product has two unique fragments (m/z 557 and 149). These distinctive fragments were further validated by using a computer program that predicts logical mass fragments and performing GC-MS of deuterated PFPA-atenolol and PFPA-propranolol and of the PFPA-alpha-hydroxy metabolite of metoprolol. By using the unique mass fragments, none of the pilot fatality cases were found to contain more than one beta-blocker. Therefore, these mass ions can be used for differentiating and simultaneously analyzing these structurally similar beta-blockers in biological samples.