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Using LC Retention Times in Organic Structure Determination: Drug Metabolite Identification

[ Vol. 12 , Issue. 2 ]

Author(s):

William L. Fitch*, Cyrus Khojasteh, Ignacio Aliagas and Kevin Johnson   Pages 93 - 100 ( 8 )

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.

Keywords:

Drug metabolite identification, liquid chromatography, mass spectrometry (MS), RT prediction, RT, CHI system.

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

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