Background: This study aimed to develop a simultaneous determination method for tramadol and its\ndesmethylates in human plasma using isocratic liquid chromatography coupled to tandem mass spectrometry and\nto validate it for pharmacokinetic evaluation in patients with cancer pain or non-cancer pain.\nMethods: The pretreatments for human plasma involved protein precipitation using acetonitrile and methanol\nunder basic conditions. Tramadol, O-desmethylate, N-desmethylate, and N,O-didesmethylate were separated on an\noctadecylsilyl column filled with 3-Ã?¼m particles using isocratic mixture of methanol and 0.15 % formic acid in water\n(35:65, v/v). The mass spectrometer was run in positive ion multiple reaction monitoring mode. This method was\napplied to the determination of plasma samples in patients treated with oral tramadol.\nResults: The chromatographic total run time was 10 min. The calibration curves in human plasma of\ntramadol, O-desmethylate, N-desmethylate, and N,O-didesmethylate were linear over the concentration ranges\nof 12.5ââ?¬â??1600, 2.5ââ?¬â??320, 2.5ââ?¬â??320, and 2.5ââ?¬â??320 ng/mL, respectively. The lower limits of quantitation of tramadol\nand its desmethylates in human plasma were 12.5 and 2.5 ng/mL. Their extraction recoveries were 85.5ââ?¬â??106.\n3 %. The intra-day and inter-day precisions and accuracies were 1.6ââ?¬â??10.2 % and 89.2ââ?¬â??106.2 % for all analytes.\nThe plasma concentration ranges of tramadol, O-desmethylate, N-desmethylate, and N,O-didesmethylate were 18.2ââ?¬â??564,\n11.8ââ?¬â??137, 4.9ââ?¬â??250, and 6.1ââ?¬â??147 ng/mL in cancer patients, and 32.8ââ?¬â??670, 7.0ââ?¬â??84.8, 5.1ââ?¬â??317, and 6.7ââ?¬â??85.2 ng/mL,\nrespectively, in non-cancer patients.\nConclusions: The present method with acceptable analytical performance can be helpful for evaluating the\npharmacokinetics of oral tramadol, including the determination of its desmethylates, for patients with cancer pain or noncancer\npain in clinical settings.
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