Evaluation of preparative high performance liquid chromatography and cryoprobe-nuclear magnetic resonance spectroscopy for the early quantitative estimation of drug metabolites in human plasma.
Definitive information on the metabolism of a drug candidate in humans is achieved through dosing radiolabelled drug as part of a clinical study, and is typically conducted post-proof of concept in Phase III of the clinical development plan. Here we describe a novel approach, using preparative high performance liquid chromatography and cryoprobe-nuclear magnetic resonance spectroscopy, to determine the human systemic exposure to a drug and its metabolites using samples derived from Phase I clinical studies. Using the described methodology, novel human plasma metabolites, as low as 10 ng/ml can be detected and quantified. This provides an opportunity, early in the development process to understand the potential role of metabolites in the safety and efficacy of drugs in humans.
Dear
G J
GJ
Structural ID Group, Toxicokinetics and Biotransformation, PCD DMPK Department, GlaxoSmithKline, Park Road, Ware, Hertfordshire SG12 0DP, UK. gordon.j.dear@gsk.com
Roberts
A D
AD
Beaumont
C
C
North
S E
SE
D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D017321:Clinical Trials, Phase I as Topic; D016903:Drug Monitoring / Q000379:methods; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000295:instrumentation / Q000379:methods*; D004364:Pharmaceutical Preparations / Q000097:blood* / Q000378:metabolism*
D004364:Pharmaceutical Preparations