Preclinical Pharmacokinetics of Triptolide: A Potential Antitumor Drug.

Abstract

Triptolide, a bioactive component in Tripterygium wilfordii extracts, possess strong antiproliferative activity on all 60-National Cancer Institute (NCI) cancer cell lines. However, the widespread use of triptolide in the clinical practice is greatly limited for its multi-organ toxicity and narrow therapeutic window. All the toxic characteristics of triptolide are associated with the pharmacokinetics especially its distribution and accumulation in the target organ. The literature review was done using PubMed search, SciFinder and Google Scholar databases with specific keywords such as triptolide, pharmacokinetics, drug-drug interaction, transporters, metabolism, modification to collect the related full-length articles and abstracts from 2000 to 2018. Oral triptolide is rapidly and highly absorbed. Grapefruit juice affects oral absorption, increasing the area under the concentration-time curve (AUC) by 153 % and the maximum concentration (Cmax) by 141 %. The AUC and the Cmax are not dose proportional. Triptolide distributes into the liver, heart, spleen, lung and kidney. Biotransformation of triptolide in rats includes hydroxylation, sulfate, glucuronide, N-acetylcysteine (NAC) and Glutathione (GSH) conjugation and combinations of these pathways. Less than 4 % of triptolide was recovered from the feces, bile and urine within 24 h. After repeating dosage, triptolide was eliminated quickly without accumulation in vivo. As a substrate of P-glycoprotein (P-gp) and CYP3A4, triptolide could have clinically significant pharmacokinetic interactions with those proteins substrates/inhibitors. The findings of this review confirm the importance of pharmacokinetic character for understanding the pharmacology and toxicology of triptolide.