Rapid intestinal glucuronidation and hepatic glucuronide recycling contributes significantly to the enterohepatic circul
- PDF / 1,683,963 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 36 Downloads / 150 Views
TOXICOKINETICS AND METABOLISM
Rapid intestinal glucuronidation and hepatic glucuronide recycling contributes significantly to the enterohepatic circulation of icaritin and its glucuronides in vivo Yi Rong1,2,3 · Yifan Tu2 · Taijun Yin2 · Zhiyun Meng1 · Guifang Dou1 · Ming Hu2 Received: 12 December 2019 / Accepted: 12 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Icaritin (ICT), a prenylflavonoid derivative extracted from the Epimedium genus, has exhibited antitumor effects in hepatocellular carcinoma (HCC) cells and safety and tolerance in clinical settings. However, ICT exhibits low blood concentration and the in vivo dominant plasma species of ICT is glucuronides [icaritin-3-glucuronide (G1), icaritin-7-glucuronide (G2) and icaritin-3, 7-diglucuronide (DIG)]. Therefore, how ICT reaches the liver and exerts its effect with low toxicity remains unknown. Therefore, pharmacokinetic experiments (p.o. 5 mg/kg with/out 50 mg/kg inhibitor combo), intestinal perfusion (2 μM ICT), portal vein infusion (1.6 μM ICT, 7.1 μM G1, 6.8 μM G2 and 4.4 μM DIG), and in vitro studies (the concentration range of substrates: 0.3–10 μM) were conducted in the present study. Ultimately, ICT was shown to undergo glucuronidation by the intestine and subsequent uptake by hepatocytes via organic anion transporting peptides (OATPs) as conjugates, followed by biliary excretion mainly as diglucuronide. In conclusion, we found for the first time that the intestine is considered as the major metabolic organ, liver as the main recycling organ for the enterohepatic recycling (EHR) of ICT. Moreover, DIG is the main species in the systemic circulation following oral administration of ICT which explains the low toxicity of ICT in clinical settings. Keywords Icaritin · Enterohepatic recycling (EHR) · Diglucuronidation · Hepatocellular carcinoma (HCC)
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02867-3) contains supplementary material, which is available to authorized users. * Guifang Dou [email protected] * Ming Hu [email protected] 1
Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, People’s Republic of China
2
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
3
Department of Pharmacy, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
Icaritin (ICT) is a prenylflavonoid derivative from the genus Epimedium (Berberidaceae), a traditional Chinese herbal medicine. ICT is recognized as a candidate for the therapy of hepatocellular carcinoma (HCC) and is now under the phase III clinical trial (ClinicalTrials.gov Identifier: NCT03236636). HCC is a primary malignancy of the liver and is the third leading cause of cancer-related deaths worldwide (Llovet et al. 2015). Due to the high toxicity and weak response of the currently marketed drugs (Crespo-Ortiz and Wei 2012; Singh et al. 2014), there is a
Data Loading...
