Pharmacokinetics, Tissue Distribution, and Tentative Metabolite Identification of Sauchinone in Mice by Microsampling and HPLC-MS/MS Methods

Abstract

Sauchinone, a biologically active lignan found in Saururus chinensis (Saururaceae), exerts various biological activities against jaundice, inflammatory disease, hepatic steatosis, and oxidative injury. Despite its diverse applications, there exists some information about sauchinone's pharmacokinetics but its tissue distribution, metabolism, and tentative metabolites have not been reported yet. Thus we investigated the pharmacokinetics of sauchinone in mice using microsampling and HPLC-MS/MS methods. Sauchinone presented linear pharmacokinetics at intravenous doses 7.5-20 mg/kg and oral doses 20-500 mg/kg. However, the metabolism of sauchinone was saturated and this agent presented nonlinear pharmacokinetics at 50 mg/ kg in the intravenous study. At sauchinone 20 mg/kg the F of sauchinone was 7.76% of the oral dose despite that 77.9% of sauchinone was absorbed. This might be due to extensive metabolism of sauchinone in S9 fractions of liver and small intestine. Tentative metabolites of sauchinone by oxidation, dioxidation, methylation, demethylation, dehydrogenation, or bis-glucuronide conjugation were detected in plasma and S9 fractions of liver, intestine, and kidney. The distribution of sauchinone was considerably high (tissue-to-plasma (T/P) ratios, >1) in liver, small intestine, kidney, lung, muscle, fat, or mesentery after intravenous and oral administration and in stomach and large intestine only after oral administration. The protein binding value of sauchinone was 53.0%. These pharmacokinetic data of sauchinone provide an important basis for preclinical applications and experimental methods can be adjusted to evaluate the pharmacokinetics of natural products in mice.Key words sauchinone; pharmacokinetics; metabolite identification; Saururus chinensis; mouse Pharmacokinetic studies to investigate the absorption, distribution, metabolism, and excretion (ADME) of pharmacologically active compounds of interest are essential in the preclinical and clinical process 1,2) because ADME of compounds are fundamental to therapeutic outcome in relation with the efficacy and safety.3) Along with the usages of a large number of herbal products as adjuvant or alternative medicines, the investigation of pharmacokinetic properties in herbal products has been demanding. [4][5][6][7] In addition, the tissue distribution and metabolism studies are meaningful to elucidate the pharmacological effects relying on the specific delivery and affinity of compounds to various tissues, extensive metabolizing organs, tentative metabolites identification.7-10) At these points, the inevitable and integral reasons for pharmacokinetic investigations using mice, not like rats, are as followings: it is arduous to secure a sufficient amount of herbal product using rats and the use of various knockout or xenografted mouse models to demonstrate the pharmacological activities of herbal compounds is increasing in preclinical investigations 11,12) in terms of the different physiological and pathological conditions between mice and rats. 13,14) Abo...

Sauchinone controls hepatic cholesterol homeostasis by the negative regulation of PCSK9 transcriptional network

“…PCSK9, LDL-R, HMGCR, SREBP1, SREBP2, HNF1A, BIRC2, ANXA2 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) oligonucleotide primers were purchased from Bioneer Corp. (Daejeon, South Korea). Sauchinone was isolated from the chloroform fraction of Saururus chinensis , as previously described, and confirmed by a spectroscopic analysis 32 . The purity of sauchinone was determined to be over 95% by high performance liquid chromatography using an ultraviolet detector.…”

“…Sauchinone isolated from Saururus chinensis has hepatoprotective, anti-inflammatory, and anti-steatosis activity 26 – 31 . We previously reported that sauchinone was distributed in relatively high levels in the liver 32 . Also, sauchinone inhibits hepatic steatosis mediated by the SREBP isoform, SREBP-1c, and activates AMP-activated protein kinase (AMPK) 31 .…”

Inhibitory Effect of Sauchinone on UDP-Glucuronosyltransferase (UGT) 2B7 Activity

“…Thus, it is meaningful to predict the potential of sauchinone–zidovudine interaction through UGT2B7. To predict the inhibitory effect of sauchinone on UGT2B7-mediated zidovudine metabolism, the following values were adjusted in Equation (1): AUC i /AUC of zidovudine was 1.52 from Table 2 , C max of sauchinone in mice plasma after oral administration of 100 mg/kg sauchinone was 1.53 μM [ 24 ] instead of [I], and K i of sauchinone for Ugt2b7 in mouse liver microsomes was 3.34 μM (our unpublished data). U.S. FDA (2012) recommends clinical evaluation of sensitive substrate if AUC i /AUC of a substrate is above 1.…”

“…First, inhibition of sauchinone or zidovudine metabolites towards UGTs was not investigated. Glucuronidation, oxidation, methylation, and dehydrogenation are involved in sauchionone metabolism [ 24 ]. Glucuronindation and reduction contribute to zidovudine metabolism [ 43 ].…”

“…Sauchinone is a biologically active lignan isolated from aerial parts of S. chinensis , showing anti-inflammatory and anti-viral activities [ 22 , 23 ]. In pharmacokinetic studies, sauchinone is highly distributed to the liver where UGTs can extensively catalyze sauchinone metabolism [ 24 , 25 ]. Thus, there might be potential of sauchinone–drug interaction through UGT-mediated metabolism.…”