Pharmacokinetics and Tissue Distribution of Combined Triptolide and Paeoniflorin Regimen for Percutaneous Administration in Rats Assessed by Liquid Chromatography-Tandem Mass Spectrometry.

Yong-Mei Guan,Liang-Fei He,Chen Li-Hua,Zhenzhong Zang,Qian Shen,Hong-Ning Liu,Li-Mei Chen,Lili Liu,Wei-Feng Zhu,Dinesh Dhamecha

doi:10.1155/2021/8864273

Abstract

Triptolide (TP) has shown potential in rheumatoid arthritis (RA) treatment, but the narrow therapeutic window limits its clinical application. In clinical practice, the compatibility of Tripterygium wilfordii and Paeonia lactiflora is often used to attenuate the toxicity of TP, but its compatibility mechanism has not been fully elucidated. The aim of this study was to investigate the pharmacokinetics and tissue distribution of a combined regimen of TP and paeoniflorin (PF) after transdermal administration in male and female Sprague Dawley (SD) rats via a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The results showed that after percutaneous administration of TP and PF, there was no significant difference in AUC (0-t) (area under the curve) of TP, the peak concentration decreased by 58.17%, and the peak time was delayed. The AUC (0-t) of PF increased significantly (P < 0.01), the peak-reaching concentration and AUC (0-∞) increased, and the half-life and average retention time were shortened, indicating that TP absorption in rats may be delayed. After percutaneous administration of TP and PF, the content of TP in the heart, liver, spleen, lungs, and kidneys of male rats significantly decreased at 2 h (P < 0.05) and the drug concentration in the liver tissues significantly decreased at 2 h, 4 h, and 8 h (P < 0.05). The TP content in the spleen of female rats significantly decreased at 2 h and 4 h (P < 0.05) and also decreased in other tissues, but not significantly. After percutaneous administration of TP and PF, the PF content in the heart, liver, spleen, lungs, and kidneys of male and female rats had no significant difference. However, after percutaneous administration of TP and PF, the TP concentration in the skin increased, suggesting that the amount of TP retained in the skin increased, thereby reducing its content in blood and tissues, producing a reduction in toxicity effect.

Highlights

Triptolide (TP) is an epoxy-xylene lactone compound. e common ingredient of Tripterygium wilfordii hook, TP, is responsible for anti-inflammatory, antitumor, antifertility, and immunomodulatory effects [1,2,3]
Specificity was evaluated by comparing the chromatogram of blank plasma with that of blank plasma spiked with the mixed standard of TP (400 ng/mL) and PF (90,000 ng/mL), as previously described and that of plasma obtained from rats after administration of TP and PF after treatment for 30 min, respectively
The calibration curves constructed by plotting the peak area ratios of TP and PF to internal standard (IS) versus the nominal concentrations in the standard biological samples using linear regression analysis are listed in Table 1. e calibrations were linear over a certain range in all matrices, and the correlation coefficients (r2) of TP and PF were 0.9949 and 0.9928, respectively

Summary

Introduction

Triptolide (TP) is an epoxy-xylene lactone compound. e common ingredient of Tripterygium wilfordii hook, TP, is responsible for anti-inflammatory, antitumor, antifertility, and immunomodulatory effects [1,2,3]. TP has a clear curative effect on rheumatoid arthritis (RA), but its narrow therapeutic window and strong liver and kidney toxicity limit its safe clinical application [4]. E mechanism of transdermal administration of Tripterygium wilfordii combined with Paeonia lactiflora is unclear. Evidence-Based Complementary and Alternative Medicine e transdermal drug delivery system (TDDS) refers to a system in which drugs are administered on the surface of the skin, pass through each layer of the skin at a constant rate, enter systemic circulation, and produce systemic or local therapeutic effects [13]. E preparation of TP as a topical preparation for transdermal administration is beneficial to reduce the first-pass effects and gastrointestinal tract toxicity and enable the drug to enter the systemic circulation in a small, continuous amount so as to reduce toxicity. Long-term use alone still produces more serious toxicity to the organism

Methods

Results

Conclusion