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Determination of S-containing drug metabolites from in vitro and in vivo metabolism studies by using LC-ICP/MS

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Abstract

Recently, liquid chromatography coupled to inductively coupled plasma mass spectrometry (LC-ICP/MS) has been introduced to deal with some applications in the field of pharmaceutical, biomedical, and clinical analysis. In the case of drug research, the number of drugs and their metabolites containing detectable elements is quite limited. In this paper, LC-ICP/MS has been demonstrated to be suitable for the determination of S-containing drugs and their metabolites. In order to minimize the interference of polyatomic oxygen (m/z 32), the indirect detection of S, by means of the SO+ ion (m/z 48), was optimized. For quantification purposes, it has been encountered that the percentage of organic solvent in the mobile phase strongly affects the sensitivity. Here, corrective strategies based on calibration curves established at different solvent concentrations (solvent-zone quantification) and post-column gradient compensation have been proposed to circumvent sensitivity variations. Results obtained have shown that suitable calibration models have been built for any compound regardless of the solvent percentage at which it is eluted from the chromatographic column. To prove the applicability of this methodology, the metabolism of ethacrynic acid and tiotropium bromide has been studied in vitro and in vivo. In the first case, ethacrynic acid does not contain S in its structure, however, the major route of metabolism for this compound consists of the formation of glutathione adduct and its further degradation. In the second case, tiotropium bromide contains two S atoms in its structure.

Determination of S-containing drug metabolites from in vitro and in vivo metabolism studies by LC-ICP/MS. Quantification strategies (solvent-zone quantification and post-column gradient compensation) proposed in order to minimize the effect of organic solvent in the quantification.

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Abbreviations

COPD:

Chronic obstructive pulmonary disease

EA:

Ethacrynic acid

FIA:

Flow injection analysis

GSH:

Glutathione

NAC:

N-Acetylcysteine

NADP+ :

β-Nicotinamide adenine dinucleotide phosphate (oxidized form)

NADPH− :

β-Nicotinamide adenine dinucleotide phosphate (reduced form)

PEG:

Polyethylene glycol

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Acknowledgments

The authors thank Montse Julià and Francisco Jiménez for their technical assistance.

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Authors and Affiliations

  1. DMPK Department, Preclinical Development, Almirall, S.A., Laureà Miró 408-410, 08980-Sant Feliu de Llobregat, Barcelona, Spain

    Cristina Losada, Joan J. Albertí & Sonia Sentellas

  2. Department of Analytical Chemistry, University of Barcelona, Martí i Franquès, 1-11, 08007, Barcelona, Spain

    Javier Saurina

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  1. Cristina Losada
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  2. Joan J. Albertí
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  3. Javier Saurina
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  4. Sonia Sentellas
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Correspondence to Sonia Sentellas.

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Losada, C., Albertí, J.J., Saurina, J. et al. Determination of S-containing drug metabolites from in vitro and in vivo metabolism studies by using LC-ICP/MS. Anal Bioanal Chem 404, 539–551 (2012). https://doi.org/10.1007/s00216-012-6145-x

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  • DOI: https://doi.org/10.1007/s00216-012-6145-x

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