Comparison of Pinoresinol and its Diglucoside on their ADME Properties and Vasorelaxant Effects on Phenylephrine-Induced Model.

Yiqiong Pu,Bing Wang,Teng Zhang,Yiqing Cai,Tianling Hou,Qi Zhang,Tong Zhang

doi:10.3389/fphar.2021.695530

Abstract

Pinoresinol (PINL) and pinoresinol diglucoside (PDG), two natural lignans found in Eucommia ulmoides Oliv. (Duzhong), have several pharmacological activities. However, there is no report available on their absorption, distribution, metabolism, and elimination (ADME) properties. Given the possible wide spectrum of their application in therapeutic areas, this area should be investigated. This work studied the in vitro ADME properties of PDG and PINL, including their kinetic solubility, permeability across monolayer cells (PAMPA), protein binding, and metabolic stabilities in liver microsomes. The in vivo pharmacokinetic study and in vitro vasorelaxant effects on isolated phenylephrine-induced aortic rings of PINL and PDG were also investigated. It was found that both of their kinetic solubility in PBS (pH 7.4) was greater than 100 μM, indicating that they are both soluble compounds. The permeability investigations (P eff) by PAMPA indicated that PINL had higher permeability than PDG (p < 0.05). Both components represented moderate plasma protein binding activities (average binding rate in human plasma: PINL 89.03%, PDG 45.21%) and low metabolic rate (t 1/2 in human liver microsome: PINL 1509.5 min, PDG 1004.8 min). Furthermore, the results of pharmacokinetic studies indicated that PINL might be eliminated less quickly than PDG from the rat plasma, and its cumulative urinary excretion was much lower than that of PDG. The phenylephrine-induced aortic rings demonstrated concentration-dependent vasorelaxation in PDG, PINL, or their combination group. The vasorelaxant effects of PINL were more obvious than those of PDG, whereas the vasorelaxant effect of the combinations was significantly better than that of the single component (p < 0.05). The similarity or difference between PINL and its diglucoside in these pharmaceutical aspects may offer valuable insights into the further exploration of lignans and might contribute to relevant studies involving natural products with similar molecular structure and their glucosides.

Highlights

IntroductionCortex Eucommiae (called Duzhong in Chinese), a kind of Chinese medicinal herb, is the dried barks of Eucommia ulmoides Oliv., which is often used as an anti-hypertension agent in clinical practice (Greenway et al, 2011)
Cortex Eucommiae, a kind of Chinese medicinal herb, is the dried barks of Eucommia ulmoides Oliv., which is often used as an anti-hypertension agent in clinical practice (Greenway et al, 2011)
In terms of molecular structure, PINL and its diglucoside (PDG) can be considered PINL plus two β-D-. Glucopyranose at both ends, which increases the total solvent accessible surface areas (SASA) by 373 Å2. In polar solvents, such as PBS, the solubility of PDG is obviously higher than PINL in experiments, which is consistent with the experimental results

Summary

Introduction

Cortex Eucommiae (called Duzhong in Chinese), a kind of Chinese medicinal herb, is the dried barks of Eucommia ulmoides Oliv., which is often used as an anti-hypertension agent in clinical practice (Greenway et al, 2011). A Chinese patent drug named QuanDuzhong Capsules (containing Duzhong extracts only), has been included in the current Chinese Pharmacopeia (2020 Edition), where anti-hypertension is listed as its main indications. In the study on the components contained in the herb, the natural products identified from Cortex Eucommiae include lignans, iridoids, phenolics, flavonoids, steroid, and terpenoids among which lignans and their derivatives are the main components. In Cortex Eucommiae, the lignans mainly include bisepoxylignans, monoepoxylignans, neolignans, and sesquilignans (He et al, 2014). Bisepoxylignans are recombined compositions whose side chains of two phenylpropanoids between 7–9 and 7′–9′ are connected to form a tetrahydrofuran ring. The tetrahydrofuran ring is combined with a cis stereo configuration, and the optical rotation is mostly dextral (Wang et al, 2019)

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