Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지

Acute Hepatotoxicity and Toxicokinetics of Acetaminophen in Mice

마우스에서 아세트아미노펜의 급성간독성과 독물동태학

  • 서경원 (식품의약품안전본부, 독성부, 서울시 은평구 녹번동 5번지 122-020) ;
  • 류정상 (식품의약품안전본부, 독성부, 서울시 은평구 녹번동 5번지 122-020) ;
  • 김효정 (식품의약품안전본부, 독성부, 서울시 은평구 녹번동 5번지 122-020)
  • Published : 1997.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

As the development of a pharmaceutical product is a dynamic process which involves continuousfeed-back between non-clinical and clinical studies, the integration of pharmacokinetics into toxicity testing became increasingly important in recent years. Toxicokinetic measurements in the toxicity studies is considered to be an important scientific approach in the interpretation of the toxicology findings and the promotion of rational study design development. Primarily this research project was conducted to determine the systemic exposure achieved in acute toxicity test and its relationship to dose level and the time course of the toxicity study. Acute hepatotoxicity study and its relevant toxicokinetic study in mice were performed using acetarninophen (AA) as a model compound. The correlation between acute hepatotoxicity indices and toxicokinetic parameters following intraperitoneally administration of various dosages of AA in mice was evaluated and discussed minutely in the text. Based on these studies, single-dose toxicity testing of AA including kinetic studies was evaluated in ICR mice for 7 days and interpreted in the text. Our results from the integration of toxicokinetic monitoring into single-dose toxicity study enable to elucidate the relation of the exposure achieved in toxicity study to toxicological findings and assist in the selection of appropriate dose levels for use in repeated-dose toxicity or later studies.

Keywords

References

  1. Br. J. Pharmacol. Chemother v.26 Liver necrosis form paracetamol Boyd, E. M.;Bereczky, G. M.
  2. Proc. Natl. Acad. Sci. U.S.A. v.81 N-acetyl-p-benzoquinoneimine:A cytochrome P-450 mediated oxidation product of acetaminophen Dahlin, D. C.;Miwa, G. T.;Lu, A. Y. H.;Nelson, S. D.
  3. Life Sci. v.14 Species differences in hepatic glutathione depletion, covalent binding and hepatic necrosis after acetaminophen Davies, D. D.;Potter, W. Z.;Jollow, D.J.;Mitchell, J. R.
  4. J. Pharm. Pharmacol. v.29 Paracetamol metabolism following overdosage: Application of high-performance liquid chromatography Howie, D.;Adriaenssens, P.;Prescott, L. F.
  5. J. Pharm. Sci. v.74 Estimation of variance for harmonic mean half-lives Lam, F.C.;Hung, C. T.;Perrier, D. G.
  6. J. Pharmacol. Exp. Ther. v.187 Acetaminophen-induced hepatic necrosis. Ⅰ. Role of durg metabolism Mitchell, J. R.;Jollow, D. J.;Potter, W. Z.;Davis, D. C.;Gillette, J. R.;Brodie, B. B.
  7. Lancet v.1 Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage Prescott, L. F.;Wright, N.;Roscoe, P.;Brown, S. S.
  8. Mol. Pharmacol. v.25 Reduction and glutathione conjugation reactions of N-acetyl-p-benzoquinoneimine and two dimethylated analogues Rosen, G. M.;Rauckman, E. J.;Ellington, S. P.;Dahlin, D. C.;Christie, J. L.;Nelson, S. D.
  9. Pharmacology(Basel) v.16 Relations between hepatotoxicity and pharmacokinetics of paracetamol in rats and mice Siegers, C. P.;Strubelt, O.;Schult, A.
  10. Res. Commun. Chem. Pathol. Pharmacol. v.18 Reduction of a cetaminophen toxicity by sodium sulfate in mice Slattery, J. T.;Levy, G.