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Drug Res (Stuttg) 2015; 65(11): 602-606
DOI: 10.1055/s-0034-1395676
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Gender Differences in the Toxicokinetics of Triptolide after Single- and Multiple-dose Administration in Rats

L. Liu
1   Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, China
2   School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, China
,
J. Zhang
3   Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, China
,
Z. Wang
2   School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, China
,
D. Xu
2   School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, China
,
Z. Jiang
1   Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, China
,
T. Wang
1   Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, China
,
W. Ju
3   Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, China
,
L. Zhang
1   Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, China
› Author Affiliations
Further Information

Publication History

received 14 August 2014

accepted 20 November 2014

Publication Date:
03 February 2015 (online)

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Abstract

Triptolide is a natural compound extracted from the traditional Chinese medicine Tripterygium wilfordii Hook F with distinguishing pharmacological activities and evident toxicities. We reported previously that 28 continuous days of oral administration of triptolide in rats resulted in gender dimorphic profiles in toxicities. To better understand this issue, the toxicokinetics of triptolide was observed in this study. Rats of both sexes were administered 400 μg/kg triptolide either as a single dose or multiple doses for 28 days. Triptolide concentrations in rat plasma were determined using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The plasma concentration-time curve and toxicokinetic parameters revealed gender differences after single and repeated triptolide administration, including significantly higher area under the plasma concentration-time curve (AUC0–∞) and peak plasma concentration (Cmax), lower clearance rate (CL) and longer terminal elimination half-life (t1/2) of triptolide in females, and lower drug exposure levels and greater CL in males. The gender differential disposition of triptolide may be the cause of increased toxicity in females. Moreover, auto-inhibition of metabolism and the resulting increase in drug exposure were observed after repeated dosing. The AUC0–∞ of triptolide was increased 6-fold in females and 2-fold in males, while the CL of triptolide was significantly decreased by 84% in females and 55% in males. These results indicated that gender-related differences existed in the toxicokinetics of triptolide and long-term oral administration of triptolide resulted in drug accumulation, which might account for the gender differences in the toxicities of triptolide.

Key words

gender difference - triptolide - toxicokinetics
 

  • References

  • 1 Soldin OP, Chung SH, Mattison DR. Sex differences in drug disposition. J Biomed Biotechnol 2011; Article ID: 187103
    PubMedGoogle Scholar
  • 2 Soldin OP, Mattison DR. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2009; 48: 143-157
    CrossrefPubMedGoogle Scholar
  • 3 Chen BJ. Triptolide, a novel immunosuppressive and anti-inflammatory agent purified from a Chinese herb Tripterygium wilfordii Hook F. Leuk Lymphoma 2001; 42: 253-265
    CrossrefPubMedGoogle Scholar
  • 4 Gao Q, Shen W, Qin W et al. Treatment of db/db diabetic mice with triptolide: a novel therapy for diabetic nephropathy. Nephrol Dial Transplant 2010; 25: 3539-3547
    CrossrefPubMedGoogle Scholar
  • 5 Huynh PN, Hikim AP, Wang C et al. Long-term effects of triptolide on spermatogenesis, epididymal sperm function, and fertility in male rats. J Androl 2000; 21: 689-699
    PubMedGoogle Scholar
  • 6 Li H, Takai N, Yuge A et al. Novel target genes responsive to the anti-growth activity of triptolide in endometrial and ovarian cancer cells. Cancer Lett 2010; 297: 198-206
    CrossrefPubMedGoogle Scholar
  • 7 Han R, Rostami-Yazdi M, Gerdes S et al. Triptolide in the treatment of psoriasis and other immune-mediated inflammatory diseases. Br J Clin Pharmacol 2012; 74: 424-436
    CrossrefPubMedGoogle Scholar
  • 8 Lipsky PE, Tao XL. A potential new treatment for rheumatoid arthritis: thunder god vine. Semin Arthritis Rheum 1997; 26: 713-723
    CrossrefPubMedGoogle Scholar
  • 9 Li J, Lu Y, Xiao C et al. Comparison of toxic reaction of Tripterygium wilfordii multiglycoside in normal and adjuvant arthritic rats. J Ethnopharmacol 2011; 135: 270-277
    CrossrefPubMedGoogle Scholar
  • 10 Xue X, Gong L, Qi X et al. Knockout of hepatic P450 reductase aggravates triptolide-induced toxicity. Toxicol Lett 2011; 205: 47-54
    CrossrefPubMedGoogle Scholar
  • 11 Liu L, Jiang Z, Liu J et al. Sex differences in subacute toxicity and hepatic microsomal metabolism of triptolide in rats. Toxicology 2010; 271: 57-63
    CrossrefPubMedGoogle Scholar
  • 12 Li W, Liu Y, He YQ et al. Characterization of triptolide hydroxylation by cytochrome P450 in human and rat liver microsomes. Xenobiotica 2008; 38: 1551-1565
    CrossrefPubMedGoogle Scholar
  • 13 Zhou R, Zhang F, He PL et al. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide analog mediates immunosuppressive effects in vitro and in vivo. Int Immunopharmacol 2005; 5: 1895-1903
    CrossrefPubMedGoogle Scholar
  • 14 Liu L, Cao B, Aa J et al. Prediction of the pharmacokinetic parameters of triptolide in rats based on endogenous molecules in pre-dose baseline serum. PLoS One 2012; 7: e43389
    CrossrefPubMedGoogle Scholar
  • 15 Ni B, Jiang Z, Huang X et al. Male reproductive toxicity and toxicokinetics of triptolide in rats. Arzneimittelforschung 2008; 58: 673-680
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Shao F, Wang G, Xie H et al. Pharmacokinetic study of triptolide, a constituent of immunosuppressive chinese herb medicine, in rats. Biol Pharm Bull 2007; 30: 702-707
    CrossrefPubMedGoogle Scholar
  • 17 Liu L, Jiang Z, Huang X et al. Disappearance of sexual dimorphism in triptolide metabolism in monosodium glutamate treated neonatal rats. Arzneimittelforschung 2011; 61: 98-103
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Zhuang XM, Shen GL, Xiao WB et al. Assessment of the roles of P-glycoprotein and cytochrome P450 in triptolide-induced liver toxicity in sandwich-cultured rat hepatocyte model. Drug Metab Dispos 2013; 41: 2158-2165
    CrossrefPubMedGoogle Scholar
  • 19 Nicolson TJ, Mellor HR, Roberts RR. Gender differences in drug toxicity. Trends Pharmacol Sci 2010; 31: 108-114
    CrossrefPubMedGoogle Scholar
  • 20 Liu S, Liu Z, Zhou L et al. Active ingredients of tripterygium wilfordii impact on P450 activities using a cocktail method. Chin Pharmacol Bull 2011; 27: 276-280
    PubMedGoogle Scholar
  • 21 Zhang Y, Jiang Z, Xue M et al. Toxicogenomic analysis of the gene expression changes in rat liver after a 28-day oral Tripterygium wilfordii multiglycoside exposure. J Ethnopharmacol 2012; 141: 170-177
    CrossrefPubMedGoogle Scholar
  • 22 Xue M, Zhao Y, Li XJ et al. Comparison of toxicokinetic and tissue distribution of triptolide-loaded solid lipid nanoparticles vs. free triptolide in rats. Eur J Pharm Sci 2012; 47: 713-717
    CrossrefPubMedGoogle Scholar
  • 23 Zhang XF, Liu J, Ye F et al. Effects of triptolide on the pharmacokinetics of cyclophosphamide in rats: A possible role of cytochromeP3A4 inhibition. Chin J Integr Med 2014; 20: 534-539
    CrossrefPubMedGoogle Scholar