Title:Using LC Retention Times in Organic Structure Determination: Drug Metabolite Identification
VOLUME: 12 ISSUE: 2
Author(s):William L. Fitch*, Cyrus Khojasteh, Ignacio Aliagas and Kevin Johnson
Affiliation: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
Keywords:Drug metabolite identification, liquid chromatography, mass spectrometry (MS), RT prediction, RT, CHI system.
Abstract: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.
