title: A parallel chiral-achiral liquid chromatographic method for the determination of the stereoisomers of ketamine and ketamine metabolites in the plasma and urine of patients with complex regional pain syndrome.
abstract: A parallel chiral/achiral LC-MS/MS assay has been developed and validated to measure the plasma and urine concentrations of the enantiomers of ketamine, (R)- and (S)-Ket, in complex regional pain syndrome (CRPS) patients receiving a 5-day continuous infusion of a sub-anesthetic dose of (R,S)-Ket. The method was also validated for the determination of the enantiomers of the Ket metabolites norketamine, (R)- and (S)-norKet and dehydronorketamine, (R)- and (S)-DHNK, as well as the diastereomeric metabolites hydroxynorketamine, (2S,6S)-/(2R,6R)-HNK and two hydroxyketamines, (2S,6S)-HKet and (2S,6R)-Hket. In this method, (R,S)-Ket, (R,S)-norKet and (R,S)-DHNK and the diastereomeric hydroxyl-metabolites were separated and quantified using a C(18) stationary phase and the relative enantiomeric concentrations of (R,S)-Ket, (R,S)-norKet and (R,S)-DHNK were determined using an AGP-CSP. The analysis of the results of microsomal incubations of (R)- and (S)-Ket and a plasma and urine sample from a CRPS patient indicated the presence of 10 additional compounds and glucuronides. The data from the analysis of the patient sample also demonstrated that a series of HNK metabolites were the primary metabolites in plasma and (R)- and (S)-DHNK were the major metabolites found in urine. The results suggest that norKet is the initial, but not the primary metabolite and that downstream norKet metabolites play a role in (R,S)-Ket-related pain relief in CRPS patients.
authors.affiliation: Laboratory for Clinical Investigation, National Institute on Aging/NIH, Baltimore, MD 21224, United States.
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.forename: Swarajya Lakshmi Vattem
authors.initials: SL
authors.lastname: Venkata
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Tanga
authors.forename: James E
authors.initials: JE
authors.lastname: Bupp
authors.forename: Carol E
authors.initials: CE
authors.lastname: Green
authors.forename: Lalitha
authors.initials: L
authors.lastname: Iyer
authors.forename: Anna
authors.initials: A
authors.lastname: Furimsky
authors.forename: Michael E
authors.initials: ME
authors.lastname: Goldberg
authors.forename: Marc C
authors.initials: MC
authors.lastname: Torjman
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D000700:Analgesics / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000652:urine*; D001711:Biotransformation; D002138:Calibration; D002853:Chromatography, Liquid / Q000379:methods; D020918:Complex Regional Pain Syndromes / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000652:urine; D020719:Glucuronides / Q000097:blood / Q000378:metabolism / Q000652:urine; D006801:Humans; D007262:Infusions, Intravenous; D007649:Ketamine / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000652:urine*; D012015:Reference Standards; D015203:Reproducibility of Results; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D000700:Analgesics; D020719:Glucuronides; D007649:Ketamine