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Stereoselective interaction of tolvaptan with amiodarone under racemic metabolic impact by CYP3A5 genotypes in heart failure patients

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The diuretic effect of tolvaptan is largely blood level-dependent although it does exhibit interindividual differences according to cytochrome P450 (CYP) 3A5 genotype. This study aimed to investigate the pharmacokinetic relationship between plasma tolvaptan and its monohydroxylate enantiomers and the factors affecting their metabolism in heart failure patients.

Methods

Japanese heart failure patients (n = 88) receiving oral tolvaptan (median dosage 7.5 mg/day) were enrolled. Blood samples were collected prior to the dosing on day 6 or later after first administration to determine the plasma concentrations of tolvaptan and its monohydroxylate enantiomers. Gene polymorphisms of CYP3A5, carbonyl reductase (CBR) 1/3, and ATP-binding cassette subfamily B member (ABCB) 1 were analyzed for their impact on tolvaptan pharmacokinetics. Serum laboratory test values and concomitant use of amiodarone were evaluated as factors related to tolvaptan metabolism.

Results

The median of the sum of the 5S- and 5R-tolvaptan plasma concentrations was 48.9 (range, 15.3–100) ng/mL. CYP3A5 genotypes significantly affected the concentration ratio of all enantiomeric metabolites to tolvaptan, while the other metabolic-related gene polymorphisms had no influence. A negative correlation was found between serum albumin and the enantiomeric ratio of tolvaptan and monohydroxylate DM-4111. Concomitant use of amiodarone increased the plasma levels of whole tolvaptan but significantly decreased the metabolic ratios of 5R-tolvaptan. 5S-tolvaptan was selectively synthesized from ketone MOP-21826 by CBR1 with a substantially smaller reaction velocity compared to tolvaptan monohydroxylation by CYP3A4/5.

Conclusion

This study clarified the racemic impact of CYP3A5 genotypes on tolvaptan metabolism. Amiodarone may stereoselectively interact with R-forms rather than S-forms of tolvaptan.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

Not applicable.

Abbreviations

CYP:

Cytochrome P450

ABCB:

ATP-binding cassette subfamily B member

EDTA:

Ethylene diamine tetra acetic acid

LC-MSMS:

Liquid chromatography-tandem mass spectrometry

FDA:

Food and Drug Administration

NADPH:

Nicotinamide adenine dinucleotide phosphate

CBR:

Carbonyl reductase

SNP:

Single-nucleotide polymorphism

eGFR:

Estimated glomerular filtration rate

Km:

Michaelis constant

Vmax:

Maximum velocity

IQR:

Interquartile range

CI:

Confidence interval

OATP:

Organic anion transporter

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Acknowledgements

5R- and 5S-tolvaptan, DM-4110 (4R5R/4S5S-diols), DM-4111 (4S5R/4R5S-diols), and DM-4119 (3S5R/3R5S-diols) were generously provided by Otsuka Pharmaceutical Co., Ltd.

Funding

This study was performed with the support from the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number JP19H00346.

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Authors and Affiliations

  1. Department of Hospital Pharmacy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan

    Shunta Akutsu, Yasuaki Mino, Takafumi Naito, Kohei Hoshikawa & Junichi Kawakami

  2. Department of Cardiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan

    Masao Saotome & Yuichiro Maekawa

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  1. Shunta Akutsu
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  2. Yasuaki Mino
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Contributions

All authors contributed to the design of this study. SA and KH conducted data collection. SA analyzed the data and drafted the manuscript with advice from YM. All authors contributed substantially to its revision. All authors read and approved the final draft for submission.

Corresponding author

Correspondence to Yasuaki Mino.

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Ethics approval

The Ethics Committee of Hamamatsu University School of Medicine approved the study protocol (20–105). This study was conducted in accordance with the guidelines of the Declaration of Helsinki and Medical and Health Research Involving Human Subjects in Japan.

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Informed consent was obtained from each of the participating individuals.

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The authors declare no competing interests.

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Akutsu, S., Mino, Y., Naito, T. et al. Stereoselective interaction of tolvaptan with amiodarone under racemic metabolic impact by CYP3A5 genotypes in heart failure patients. Eur J Clin Pharmacol 78, 1311–1320 (2022). https://doi.org/10.1007/s00228-022-03341-y

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