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.
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.
Moaddel
Ruin
R
Laboratory for Clinical Investigation, National Institute on Aging/NIH, Baltimore, MD 21224, United States.
Venkata
Swarajya Lakshmi Vattem
SL
Tanga
Mary J
MJ
Bupp
James E
JE
Green
Carol E
CE
Iyer
Lalitha
L
Furimsky
Anna
A
Goldberg
Michael E
ME
Torjman
Marc C
MC
Wainer
Irving W
IW
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
D000700:Analgesics; D020719:Glucuronides; D007649:Ketamine