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Drug Metabolism & Disposition

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Isolation and Identification of 3,4-Seco-Solanidine-3,4-dioic acid (SSDA) as a Urinary Biomarker of Cytochrome P450 2D6 (CYP2D6) Activity

Andrew C Behrle, Justin Douglas, J. Steven Leeder and Leon van Haandel
Drug Metabolism and Disposition July 25, 2022, DMD-AR-2022-000957; DOI: https://doi.org/10.1124/dmd.122.000957
Andrew C Behrle
1Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Kansas City, United States
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Justin Douglas
2NMR Core Laboratory, University of Kansas, United States
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J. Steven Leeder
3Children's Mercy Res Inst, Children's Mercy Kansas City, United States
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  • For correspondence: sleeder@cmh.edu
Leon van Haandel
1Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Kansas City, United States
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Abstract

Cytochrome P450 2D6 (CYP2D6), is responsible for the metabolism and elimination of approximately 25% of clinically used drugs, including antidepressants and antipsychotics, and its activity varies considerably on a population basis primary due to genetic variation. CYP2D6 phenotype can be assessed in vivo following administration of an exogenous probe compound, such as dextromethorphan or debrisoquine, but use of a biomarker that does not require administration of an exogenous compound (i.e., drug) has considerable appeal for assessing CYP2D6 activity in vulnerable populations, such as children. The goal of this study was to isolate, purify and identify an "endogenous" urinary biomarker (M1; m/z 444.3102) of CYP2D6 activity reported previously. Several chromatographic separation techniques (reverse phase HPLC, cation exchange and analytical reverse phase UPLC) were used to isolate and purify 96 μg of M1 from 40 L of urine. Subsequently, 1D and 2D NMR, and functional group modification reactions were used to elucidate its structure. Analysis of mass spectrometry and NMR data revealed M1 to have similar spectroscopic features to the nitrogen-containing steroidal alkaloid, solanidine. 2D NMR characterization by HMBC, COSY, TOCSY, and HSQC-TOCSY proved to be invaluable in the structural elucidation of M1; derivatization of M1 revealed the presence of two carboxylic acid moieties. M1 was determined to be a steroidal alkaloid with a solanidine backbone that had undergone C-C bond scission to yield 3,4-seco-solanidine-3,4-dioic acid (SSDA). SSDA may have value as a dietary biomarker of CYP2D6 activity in populations where potato consumption is common.

Significance Statement Endogenous biomarkers of processes involved in drug disposition and response may allow improved individualization of drug treatment, especially in vulnerable populations, such as children. Given that several CYP2D6 substrates are commonly used in pediatrics and the ubiquitous nature of potato consumption in western diets, SSDA has considerable appeal as non-invasive biomarker of CYP2D6 activity to guide treatment with CYP2D6 substrates in children and adults.

  • CYP2D6
  • metabolite identification
  • pharmacogenetics
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 50 (8)
Drug Metabolism and Disposition
Vol. 50, Issue 8
1 Aug 2022
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Identification of SSDA as a Biomarker of CYP2D6 Activity

Andrew C Behrle, Justin Douglas, J. Steven Leeder and Leon van Haandel
Drug Metabolism and Disposition July 25, 2022, DMD-AR-2022-000957; DOI: https://doi.org/10.1124/dmd.122.000957

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Identification of SSDA as a Biomarker of CYP2D6 Activity

Andrew C Behrle, Justin Douglas, J. Steven Leeder and Leon van Haandel
Drug Metabolism and Disposition July 25, 2022, DMD-AR-2022-000957; DOI: https://doi.org/10.1124/dmd.122.000957
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