In Vivo to In Vitro Effects of Six Bioactive Lignans of Wuzhi Tablet (Schisandra Sphenanthera Extract) on the CYP3A/P-glycoprotein–Mediated Absorption and Metabolism of Tacrolimus

Abstract

We recently reported that Wuzhi tablet (WZ; Schisandra sphenanthera extract) can inhibit P-glycoprotein (P-gp)-mediated efflux and CYP3A-mediated metabolism of tacrolimus (FK506) and thus increase the blood concentrations of FK506. Major active lignans of WZ include schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, and schisantherin A. Whether and how these six lignans affect the pharmacokinetics of FK506 remains unclear. Therefore, this study aimed to investigate the effects of these lignans on the first-pass absorption and metabolism of FK506 and the involved mechanisms in vitro and in vivo. The results showed that whole-blood concentrations of FK506 were increased to different degrees following coadministration of the six lignans, respectively. Schisandrol B showed the strongest effect on the increase of the area under the concentration-time curve, the oral bioavailability, the gut processes affecting availability, and the hepatic availability of FK506. The reduction of intestinal first-pass effect contributed most to the increase in oral bioavailability of FK506 when coadministered with schisandrol B. In vitro transport experiment showed that schisandrin A, schisandrin B, and schisandrol B inhibited P-gp-mediated efflux of FK506. In vitro metabolism study showed that the inhibitory effect of these six lignans on FK506 metabolism was dose-dependent. In conclusion, the exposure of FK506 in rats was increased when coadministered with these lignans, and schisandrol B showed the strongest effect. Lignans of WZ inhibited P-gp-mediated efflux and CYP3A-mediated metabolism of FK506, and the reduction of intestinal first-pass affected by the lignans was the major cause of the increased FK506 oral bioavailability.

Prediction of Drug–Drug Interaction between Tacrolimus and Principal Ingredients of Wuzhi Capsule in Chinese Healthy Volunteers Using Physiologically‐Based Pharmacokinetic Modelling

“…Therefore, in the enzyme kinetic model of tacrolimus, the demethylation and hydroxylation pathways were usually selected. Nevertheless, STA was found to have poor effect on the transport ratio of tacrolimus in Caco-2 cell [9]. Although SIA inhibited the efflux of tacrolimus completely at the concentration of 100 lM, there was little effect on the transportation of tacrolimus while the concentration of SIA was 50 lM [36], which was much higher than the estimated concentration of SIA in the human intestine (2.7-4.5 lM), which was calculated based on the daily dose of Wuzhi capsule and the reported volume of human gastrointestinal fluid [37].…”

“…This discrepancy might be explained by the liver microsome of different species and the choice of probe substrate. Furthermore, DDI studies in rats showed that the blood exposure of tacrolimus could be increased to 2.48-and 2.37-fold by STA and SIA, respectively, with an oral dose of 0.024 mmol/kg [9]. Briefly, STA and SIA could inhibit the metabolism of tacrolimus in both in vitro and animal experiments.…”

Metabolic mapping of Schisandra sphenanthera extract and its active lignans using a metabolomic approach based on ultra high performance liquid chromatography with high‐resolution mass spectrometry

“…The metabolic profile of drugs and drug candidates can be clearly elucidated through combining in vitro incubation mixtures and in vivo animal models . The pharmacokinetics of the six bioactive lignans in WZ were also measured and we found that most of the lignans reached the highest blood concentration at 2 h and nearly eliminated 24 h after an oral dose to rats . However, the complete metabolite profile of WZ and its active lignans remains unclear in vitro and in vivo , and needs to be further clarified to better understand efficacy or toxicity of WZ.…”

A Molecular Aspect in the Regulation of Drug Metabolism: Does PXR-Induced Enzyme Expression Always Lead to Functional Changes in Drug Metabolism?

“…In one such example, co-administration of WWZ has been shown to increase the oral bioavailability of FK506 (Tacrolimus) [53]. WWZ or its constituent compounds have also been shown to increase the bioavailability of cyclosporine A and paclitaxel in animal models [54–56]. The metabolism of FK506 mainly occurred in the liver and small intestine via CYP3A [53].…”