2. Academic Validation
  3. Intestinal absorption mechanism of rotundic acid: Involvement of P-gp and OATP2B1

Intestinal absorption mechanism of rotundic acid: Involvement of P-gp and OATP2B1

  • J Ethnopharmacol. 2022 May 10;289:115006. doi: 10.1016/j.jep.2022.115006.
Haihua Shang 1,  Yinghui Sun 2,  Ze Wang 3,  Ying Zhou 4,  Huajiao Yang 4,  Xiaoyan Ci 2,  Tao Cui 2,  Yuanyuan Xia 5,  Yuan Gu 5,  Maoliang Liao 6,  Quansheng Li 4,  Duanyun Si 7,  Changxiao Liu 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300000, China; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China.
  • 2 Research Center of Bio-Technology, Tianjin Institute of Pharmaceutical Research, Tianjin, 300000, China.
  • 3 College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China.
  • 4 State Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300000, China.
  • 5 Tianjin Institute of Pharmaceutical Research, Tianjin, 300000, China; Research Unit for Drug Metabolism, Chinese Academy of Medical Sciences, Beijing, 100730, China.
  • 6 State Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300000, China; Tianjin Ringpu Bio-technology Co., Ltd., Tianjin, 300308, China. Electronic address: liaomaoliang@163.com.
  • 7 State Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300000, China; Tianjin Institute of Pharmaceutical Research, Tianjin, 300000, China; Research Unit for Drug Metabolism, Chinese Academy of Medical Sciences, Beijing, 100730, China.
  • 8 State Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300000, China; Tianjin Institute of Pharmaceutical Research, Tianjin, 300000, China; Research Unit for Drug Metabolism, Chinese Academy of Medical Sciences, Beijing, 100730, China. Electronic address: liuchangxiao@163.com.
PMID: 35051604 DOI: 10.1016/j.jep.2022.115006
Abstract

Ethnopharmacological relevance: Ilicis Rotundae Cortex (IRC), the dried barks of Ilex rotunda Thunb. (Aquifoliaceae), has been used for the prevention or treatment of colds, tonsillitis, dysentery, and gastrointestinal diseases in folk medicine due to its Antibacterial and anti-inflammatory effects. However, there is no report about the intestinal absorption of major compounds that support traditional usage.

Aim of study: Considering the potential of rotundic acid (RA) - major biologically active pentacyclic Triterpenes found in the IRC, this study was purposed to uncover the oral absorption mechanism of RA using in situ single-pass intestinal perfusion (SPIP) model, in vitro cell models (Caco-2, MDCKII-WT, MDCKII-MDR1, MDCKII-BCRP, and HEK293-OATP2B1 cells) and in vivo pharmacokinetics studies in rats.

Materials and methods: The molecular properties (solubility, lipophilicity, and chemical stability) and the effects of principal parameters (time, compound concentrations, pH, paracellular pathway, and the different intestinal segments) were analyzed by liquid chromatography-tandem mass spectrometry. The susceptibility of RA to various inhibitors, such as P-gp inhibitor verapamil, BCRP Inhibitor Ko143, OATP 2B1 inhibitor rifampicin, and absorption enhancer EGTA were assessed.

Results: RA was a compound with low water solubility (12.89 μg/mL) and strong lipophilicity (LogP = 4.1). RA was considered stable in all media during the SPIP and transport studies. The SPIP and cell experiments showed RA was moderate absorbed in the intestines and exhibited time, concentration, pH, and segment-dependent permeability. In addition, results from the cell model, in situ SPIP model as well as the in vivo pharmacokinetics studies consistently showed that verapamil, rifampicin, and EGTA might have significant effect on the intestinal absorption of RA.

Conclusion: The mechanisms of intestinal absorption of RA might involve multiple transport pathways, including passive diffusion, the participation of efflux (i.e., P-gp) and influx (i.e., OATP2B1) transporters, and paracellular pathways.

Keywords

Absorption mechanism; OATP2B1; P-gp; Passive diffusion; Rotundic acid.

Figures
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  • HY-10010
    99.97%, BCRP/ABCG2抑制剂
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