Application of QuantitativeNMRin Drug Metabolism Studies

Abstract

Quantitation of small drug molecules and their metabolites in biological fluids such as blood, plasma, and urine is frequently performed by liquid chromatography–mass spectrometry (LC-MS) technique, which requires the availability of reference standards. Frequently, there is a need to know the concentrations of drug-related components in biological samples for which no reference standards exist. An alternative method of obtaining quantitative information on analytes (whose reference standards do not exist) is by quantitative nuclear magnetic resonance (qNMR). This technique is useful in various metabolism studies conducted at all stages of drug discovery and development. Examples of the application of qNMR in early discovery include pharmacological evaluation of metabolites and obtaining mass balance information. The ability to quantitate metabolites by qNMR can greatly facilitate studies designed to address metabolites in safety testing (MIST) because exposure values can easily be determined once the concentrations of metabolites are known. The ability to obtain mass balance information using 19F-NMR is also demonstrated in this article. The potential application of qNMR in conducting early human absorption, distribution, metabolism and excretion (ADME) studies with fluorinated compounds is also discussed.