Absorption Characteristics of Combination Medication of Realgar and Indigo Naturalis: In Vitro Transport across MDCK-MDR1 Cells and In Vivo Pharmacokinetics in Mice after Oral Administration

Author:

Zhang Miao1,Guo Lin2,Lin Long-Fei3,Qu Chang-Hai2,Yin Xing-Bin2,Luo Shi-Lin2,Zhang Xin2,Zhang Hai-Ying2,Liang Xiao4,Guan Jun2ORCID,Ni Jian25ORCID

Affiliation:

1. Xiyuan Hospital, China Academy of Chinese Medical Sciences and Beijing Key Lab of TCM Pharmacology, Beijing 100091, China

2. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China

3. Institute Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China

4. Shanghai Binuo Medical Instrument Co., Ltd., Shanghai 201414, China

5. Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China

Abstract

Realgar and indigo naturalis are clinically combined to treat varieties of leukemia. Exploring the drug-drug interactions might be beneficial to find active substances and develop new targeted drugs. This study aimed at exploring the change of arsenic concentration in mice and across MDCK-MDR1 cells and the cytotoxicity on K562 cells when realgar and indigo naturalis were combined. In the presence or absence of indigo naturalis, pharmacokinetics and cell-based permeability assays were used to evaluate the change of arsenic concentration, and K562 cell line was applied to evaluate the change of cytotoxicity. The drug concentration-time profiles exhibited that the combination medication group generated higher AUC, thalf, and longer MRT for arsenic, compared with the single administration of realgar. The apparent permeability coefficients (Papp) of bidirectional transport in MDCK-MDR1 cell permeability experiments showed that arsenic permeability obviously went up when indigo naturalis was incubated together. The combination medication significantly decreased the cell viability of K562 cells when both the concentration of realgar and the concentration of indigo naturalis were nontoxic. The pharmacokinetic research, the MDCK-MDR1 based permeability study, and the K562 cytotoxicity study were united together to verify the combination medication of realgar and indigo naturalis enhanced the absorption and the permeability across cells for arsenic and effectively inhibited the proliferation of K562 cell line. The molecular binding of As4S4 and indirubin was analyzed by computational study. It is predicted that the formation of the complex [As4S4Indirubin] involves noncovalent interaction that changes the concentration of arsenic.

Funder

National Natural Science Foundation of China

Publisher

Hindawi Limited

Subject

Complementary and alternative medicine

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