William L. Fitch*, Cyrus Khojasteh, Ignacio Aliagas and Kevin Johnson Pages 93 - 100 ( 8 )
Background: There is a continued need for improvements in the efficiency of metabolite structure elucidation.
Objective: We propose to take LC Retention Time (RT) into consideration during the process of structure determination.
Methods: Herein, we develop a simple methodology that employs a Chromatographic Hydrophobicity Index (CHI) framework for standardizing LC conditions and introduce and utilize the concept of a predictable CHI change upon Phase 1 biotransformation (CHIbt). Through the analysis of literature examples, we offer a Quantitative Structure-Retention Relationship (QSRR) for several types of biotransformation (especially hydroxylation) using physicochemical properties (clogP, hydrogen bonding).
Results: The CHI system for retention indexing is shown to be practical and simple to implement. A database of CHIbt values has been created from re-incubation of 3 compounds and from analysis of an additional 17 datasets from the literature. Application of this database is illustrated.
Conclusion: In our experience, this simple methodology allows complementing the discovery efforts that saves resources for in-depth characterization using NMR.
Drug metabolite identification, liquid chromatography, mass spectrometry (MS), RT prediction, RT, CHI system.
Department of Gastroenterology and Hepatology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, Department of Drug Metabolism and Pharmacokinetics 1 DNA Way MS 412a, Genentech Inc., South San Francisco, CA 94080, Discovery Chemistry, 1 DNA Way, Genentech Inc., South San Francisco, CA 94080, Department of Drug Metabolism and Pharmacokinetics 1 DNA Way MS 412a, Genentech Inc., South San Francisco, CA 94080