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Gender differences in pharmacokinetics and tissue distribution of 4-n-nonylphenol in rats

  • Toxicokinetics and Metabolism
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Abstract

The aim of this study was to newly identify and investigate the gender differences in pharmacokinetics (PKs) and tissue distribution of 4-n-nonylphenol (4-n-NP) in both male and female Sprague–Dawley rats. For this study, a UPLC–ESI–MS/MS system for 4-n-NP was developed as a sensitive and rapid analysis method and validated according to the accepted criteria of the international guidelines. The method was finally applied to the analysis of plasma, urine, feces, and nine different tissue samples of rats. PK parameters were calculated after single oral or intravenous administration of 4-n-NP at a dose of 10 or 50 mg/kg. Mean half-life of 4-n-NP in female rats was shorter and its clearance was larger for all doses than those in male rats. There were statistically significant differences in excretion patterns of urine and feces between male and female rats. Distribution of nine different tissues for 4-n-NP was greater in male than in female, and 4-n-NP was highly distributed in the liver or kidney. It was also specific that the distribution of 4-n-NP into brain was considerable. These results suggest that there are gender differences in the PKs of 4-n-NP in rats. Although, 4-n-NP is known to be a reproductive toxicant, reports on its PKs, excretion pattern, tissue distribution, and gender difference are limited. Therefore, our results will be useful data for gender differences as well as toxicokinetic information for 4-n-NP. In addition, it is expected to be very important for future risk assessment and PBPK model establishment of 4-n-NP.

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Abbreviations

UPLC–ESI–MS/MS:

Ultrahigh performance liquid chromatography–electrospray ionization-tandem mass spectrometer

4-n-NP:

4-n-nonylphenol

4-t-OP:

4-tert-octylphenol

BPA:

Bisphenol A

BPF:

Bisphenol F

PFOA:

Perfluorooctanoic acid

PFHxS:

Perfluorohexane sulfonic acid

PFNA:

Perfluorononanoic acid

PFDA:

Perfluorodecanoic acid

CYP:

Cytochrome P450

IV:

Intravenous

GI:

Gastro-intestinal

LLE:

Liquid-liquid extraction

PP:

Protein precipitation

SPE:

Solid-phase extraction

HPLC:

High-performance liquid chromatography

LC–UV:

Liquid chromatography–ultraviolet

GC:

Gas chromatography

MRM:

Multiple reaction monitoring

LLOQ:

Lower limit of quantitation

IS:

Internal standard

QC:

Quality control

CV:

Coefficient of variation

PK:

Pharmacokinetic

PBPK:

Physiologically based pharmacokinetic

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Acknowledgements

This research was supported by a Grant (17162MFDS117) in 2017 funded by the Ministry of Food and Drug Safety, Republic of Korea.

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    Authors and Affiliations

    1. College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea

      Seung-Hyun Jeong, Ji-Hun Jang & Yong-Bok Lee

    2. College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-Si, Gyeonggi-Do, 13488, Republic of Korea

      Hea-Young Cho

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    1. Seung-Hyun Jeong
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    Correspondence to Hea-Young Cho or Yong-Bok Lee.

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    Ethical approval

    Animal experiment was approved by Chonnam National University Animal Experimental Ethics Committee, Republic of Korea (approval number: CNU IACUC-YB-2017-45). This study was performed according to revised Guidelines for Ethical Conduct in the Care and Use of Animals and rules of Good Laboratory Practice.

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    Jeong, SH., Jang, JH., Cho, HY. et al. Gender differences in pharmacokinetics and tissue distribution of 4-n-nonylphenol in rats. Arch Toxicol 93, 3121–3139 (2019). https://doi.org/10.1007/s00204-019-02581-9

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