Berberine analogue IMB-Y53 improves glucose-lowering efficacy by averting cellular efflux especially P-glycoprotein efflux.
OBJECTIVE
Cellular efflux transporters, especially P-glycoprotein (P-gp), impel berberine (BBR) out of cells, and therefore reduce bioavailability of the compound. This study was designed to overcome efflux of BBR using P-gp as a target.


METHODS
Molecular docking study was done to identify BBR analogues that were with low affinity to P-gp. Flow cytometry was used to determine cellular efflux of chemicals. Pharmacokinetic study was performed in Wistar rats, following oral administration of the study compounds. The efficacies of chemicals on glucose homeostasis were determined both in cultured cells and diabetic KK-Ay and db/db mice.


RESULTS
In the molecular docking study, we found that among BBR analogues pseudo-berberine (IMB-Y53) has low affinity to P-gp. IMB-Y53 was retained in Caco-2, HL-7702 and C2C12 cells for a significantly longer period of time than BBR did. P-gp inhibitor tetrandrine (Tet) abolished the efflux of BBR at different extent depending on the expression level of P-gp; however, Tet had no impact on IMB-Y53 efflux. BBR increased P-gp expression dose-dependently in intestinal and liver cells; IMB-Y53 also up-regulated P-gp but at a much lower level as compared with BBR. Administered at equal dose in rats, the maximum plasma concentration (C(max)) and area under concentration-time curve (AUC(0-24)) of IMB-Y53 were 1.61 and 2.27-fold of those of BBR, respectively, indicating an improved bioavailability. IMB-Y53 stimulated glucose utility in cultured cells with a degree similar to that of BBR, but exhibited enhanced glucose-lowering efficacy in KK-Ay and db/db diabetic mice.


CONCLUSIONS
These results suggest that overcoming cellular efflux especially P-gp's function improves bioavailability and hypoglycemic effect of BBR.
Department of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Yong-Qiang
YQ
Shan
Gang
G
Ren
Yan-Xiang
YX
Wang
Jing
J
Pang
Zhi-Yun
ZY
Zhao
Jing
J
Yao
Xue-Fu
XF
You
Shu-Yi
SY
Si
Dan-Qing
DQ
Song
Wei-Jia
WJ
Kong
Jian-Dong
JD
Jiang
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001599:Berberine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D001682:Biological Availability; D001786:Blood Glucose / Q000378:metabolism; D018938:Caco-2 Cells; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D056004:Molecular Dynamics Simulation; D012313:RNA / Q000737:chemistry / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D001599:Berberine; D012313:RNA