Quantitative dynamic nuclear polarization-NMR on blood plasma for assays of drug metabolism.
Analytical platforms for the fast detection, identification and quantification of circulating drugs with a narrow therapeutic range are vital in clinical pharmacology. As a result of low drug concentrations, analytical tools need to provide high sensitivity and specificity. Dynamic nuclear polarization-NMR (DNP-NMR) in the form of the hyperpolarization-dissolution method should afford the sensitivity and spectral resolution for the direct detection and quantification of numerous isotopically labeled circulating drugs and their metabolites in single liquid-state NMR transients. This study explores the capability of quantitative in vitro DNP-NMR to assay drug metabolites in blood plasma. The lower limit of detection for the anti-epileptic drug (13)C-carbamazepine and its pharmacologically active metabolite (13)C-carbamazepine-10,11-epoxide is 0.08 µg/mL in rabbit blood plasma analyzed by single-scan (13)C DNP-NMR. An internal standard is used for the accurate quantification of drug and metabolite. Comparison of quantitative DNP-NMR data with an established analytical method (liquid chromatography-mass spectrometry) yields a Pearson correlation coefficient r of 0.99. Notably, all DNP-NMR determinations were performed without analyte derivatization or sample purification other than plasma protein precipitation. Quantitative DNP-NMR is an emerging methodology which requires little sample preparation and yields quantitative data with high sensitivity for therapeutic drug monitoring.
Lerche
Mathilde H
MH
Albeda Research, Valby, Denmark. mathilde.lerche@albeda.dk
Meier
Sebastian
S
Jensen
Pernille R
PR
Hustvedt
Svein-Olaf
SO
Karlsson
Magnus
M
Duus
Jens Ø
JØ
Ardenkjaer-Larsen
Jan H
JH
D000818:Animals; D001681:Biological Assay / Q000379:methods*; D002138:Calibration; D002220:Carbamazepine / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D004347:Drug Interactions; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D013058:Mass Spectrometry; D010949:Plasma / Q000378:metabolism*; D011817:Rabbits; D012015:Reference Standards
D002220:Carbamazepine