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Simultaneous analysis of tramadol, O‐desmethyltramadol, and N‐desmethyltramadol enantiomers in rat plasma by high‐performance liquid chromatography‐tandem mass spectrometry: Application to pharmacokinetics
Author(s) -
Godoy Ana Leonor Pardo Campos,
De Moraes Natália Valadares,
Martinez Edson Zangiacomi,
Carvalho Teresa Maria De Jesus Ponte,
Marques Maria Paula,
Lanchote Vera Lucia
Publication year - 2011
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.20914
Subject(s) - chemistry , pharmacokinetics , enantiomer , chromatography , tandem mass spectrometry , tramadol , liquid chromatography–mass spectrometry , pharmacology , mass spectrometry , analgesic , stereochemistry , medicine
Tramadol (T) is available as a racemic mixture of (+)‐ trans ‐T and (−)‐ trans ‐T. The main metabolic pathways are O‐demethylation and N‐demethylation, producing trans ‐O‐desmethyltramadol ( M1 ) and trans ‐N‐desmethyltramadol ( M2 ) enantiomers, respectively. The analgesic effect of T is related to the opioid activity of (+)‐ trans‐ T and (+)‐ M1 and to the monoaminergic action of (+/−)‐ trans ‐T. This is the first study using tandem mass spectrometry as a detection system for the simultaneous analysis of trans ‐T, M1 , and M2 enantiomers. The analytes were resolved on a Chiralpak® AD column using hexane:ethanol (95.5:4.5, v/v) plus 0.1% diethylamine as the mobile phase. The quantitation limits were 0.5 ng/ml for trans‐ T and M1 and 0.1 ng/ml for M2 . The method developed and validated here was applied to a pharmacokinetic study in rats. Male Wistar rats ( n = 6 at each time point) received a single oral dose of 20 mg/kg racemic trans ‐T. Blood samples were collected up to 12 h after drug administration. The kinetic disposition of trans‐ T and M2 was enantioselective (AUC (+)/( −) ratio = 4.16 and 6.36, respectively). The direction and extent of enantioselectivity in the pharmacokinetics of trans ‐T and M2 in rats were comparable to data previously reported for healthy volunteers, suggesting that rats are a suitable model for enantioselective studies of trans ‐T pharmacokinetics. Chirality, 2011. © 2010 Wiley‐Liss, Inc.