Evaluation potential effects of Picroside II on cytochrome P450 enzymes in vitro and in vivo.

ETHNOPHARMACOLOGY RELEVANCE: Picrorhiza scrophulariiflora Pennell, a well-known Chinese herb, has been traditionally utilized as an antioxidant and anti-inflammatory agent. One of its main bioactive components is Picroside II, a glycoside derivative. However, there is limited information on the effects of Picroside II on the activity of cytochrome P450 (CYP) enzymes nor on potential herb-drug interactions are rarely studied. AIM OF THE STUDY: The purpose of the study was to investigate the effects of Picroside II on the activity of cytochrome P450 enzymes in vitro and in vivo and its potential herb-drug interactions. MATERIALS AND METHODS: Specific probe substrates were employed to assess the effect of Picroside II on the activity of P450 enzymes. The inhibitory effects of Picroside II on CYP enzymes were assayed both in human (i.e., 1A, 2C9, 2C19, 2D6, 2E1, and 3A) and rat (i.e., 1A, 2C6/11, 2D1, 2E1, and 3A) liver microsomes in vitro. The inductive effects were investigated in rats following oral gavage of 2.5 mg/kg and 10 mg/kg Picroside II. A specific Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) method was developed to determine the formation of specific metabolites. RESULTS: Enzyme inhibition results showed that Picroside II (0.5-200 µM) had no evident inhibitory effects on rat and human liver microsomes in vitro. Interestingly, the administration of multiple doses of 10 mg/kg Picroside II inhibited the activity of CYP2C6/11 by reducing the rate of formation of 4-hydroxydiclofenac and 4-hydroxymephenytoin, while Picroside II at 2.5 mg/kg increased the activity of CYP3A by promoting the formation of 1-hydroxymidazolam and 6-hydroxychlorzoxazone in rats. In addition, there were negligible effects on CYP1A, CYP2D1, and CYP2E1 in rats. CONCLUSIONS: The results indicated that Picroside II modulated the activities of CYP enzymes and was involved in CYP2C and CYP3A medicated herb-drug interactions. Therefore, careful monitoring is necessary when Picroside II is used in combination with related conventional drugs.

Metabolites identification and species comparison of Oroxylin A, an anti-cancer flavonoid, in vitro and in vivo by HPLC-Q-TOF-MS/MS.

Oroxylin A, the main component of Scutellaria baicalensis Georigi has been widely studied due to its well-known pharmacological effects. According to previous studies, Oroxylin A with low bioavailability was converted into glucuronidation and sulphonated metabolites, which had high exposure in plasma and generated certain activities. It is necessary to study the metabolites and metabolic pathways of Oroxylin A.This study aimed to explore the metabolites of Oroxylin A in liver microsomes, primary hepatocyte incubation samples of five different species (human, monkey, dog, mouse, rat), and in bile, urine and faeces of rats.It would provide a systematic description of metabolic pathway of Oroxylin A. Also, a method of high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry detector (HPLC-Q-TOF-MS/MS) for identification of each metabolite in various biological matrices was developed.This experiment illustrated that phase II metabolites were the main form of Oroxylin A in vitro and in excretion of rats, accompanied with a small amount of phase I metabolites.Furthermore, there were obvious species differences among the metabolism in vitro, especially in phase II. Monkeys and rats may be more suitable for preclinical research than dogs and mice as non-rodent or rodent species.

Characterization of Preclinical Pharmacokinetic Properties and Prediction of Human PK Using a Physiologically Based Pharmacokinetic Model for a Novel Anti-Arrhythmic Agent Sulcardine Sulfate.

PURPOSE: Sulcardine sulfate (Sul) is a novel antiarrhythmic agent with promising pharmacological properties, which is currently being evaluated in several clinical trials as an oral formulation. To meet the medication needs of patients with acute conditions, the injection formulation of Sul has been developed. The objective of this study was to systemically investigate the pharmacokinetic profiles of Sul after intravenous infusion. METHODS: This research included the plasma protein binding and metabolic stability studies in vitro, plasma pharmacokinetics, biodistribution, excretion studies in animals, and the prediction of the clinical PK of Sul injection using a physiologically based pharmacokinetics (PBPK) model. RESULTS: The metabolic stability was similarly in dogs and humans but lower in rats. The plasma protein binding rates showed a concentration-dependent manner and species differences. The pharmacokinetic behavior after intravenous administration was linear in rats within the dose range of 30-90 mg/kg, but nonlinear in dogs within 30-60 mg/kg. Sul could be rapidly and widely distributed in multiple tissues after intravenous administration. About 12% of the parent compound were excreted via the urine and only a small fraction via bile and feces,and eight metabolites were found and identified in the rat excretion. The PBPK models were developed and simulated the observed PK date well in both rats and dogs. The PBPK model refined with human data predicted the PK characteristics of the first intravenous infusion of Sul in human. CONCLUSIONS: Our study systematically explored the pharmacokinetic characteristics of Sul and successfully developed the PBPK model to predict of its clinical PK.

Pharmacokinetics, tissue distribution and excretion study of Oroxylin A, Oroxylin A 7-O-glucuronide and Oroxylin A sodium sulfonate in rats after administration of Oroxylin A.

Oroxylin A (OA), as a natural flavonoid extracted from the root of Scutellaria baicalensis Georgi, is a candidate drug with multiple pharmacological activities. However, pharmacokinetic studies of OA have rarely been reported up to now. The present study aim to conduct a systemic evaluation on the pharmacokinetics, tissue distribution and excretion of OA in rats, with quantification of both OA and its two metabolites, Oroxylin A 7-O-glucuronide (OG) and Oroxylin A sodium sulfonate (OS) by the sensitive and rapid UPLC-MS/MS methods. The results show that OA was rapidly eliminated in vivo after a single-dose (2 mg/kg) i.v. administration of OA. The relative bioavailability of OA in all three i.g. administration groups (40, 120, and 360 mg/kg) were <2%. The AUC0-t values of OA, OG, and OS in rats show an apparent dose-proportionality. OA, OG, and OS all underwent a rapid and widespread tissue distribution after i.g. administration (120 mg/kg) of OA. Except for stomach and intestine, the major distribution tissues of OA and its two metabolites in rats were liver, kidney, respectively. And OA was more widely distributed in tissue than its metabolites. After i.g. administration (120 mg/kg) of OA, it was mainly excreted from the feces, and OG mainly excreted from bile and urine, while OS almost free of excretion. This work present a comprehensive pharmacokinetics information for further investigation of OA and its two metabolites.