Table 1.

Factors causing conflicting HDI outcomes.

Factors	Herbal Products	HDI Results	PK-Based HDI Mechanism	Ref
Administration route	Ginkgo biloba leaf extract (oral, p.o.)	G. biloba leaf extract only alters the PK of orally, but not intravenously, administered nifedipine in rats	Due to inhibition of CYP3A in intestine, not in liver	[61]
	Zingiber officinale root juice (p.o.)	Z. officinale juice decreases the oral bioavailability of cyclosporine, but the PK property of intravenous cyclosporine is not altered in rats	Due to inhibition of CYP3A and P-gp in intestine, not in liver	[62]
	Echinacea purpurea root (p.o.)	E. purpurea root extract reduced systemic clearance of midazolam following intravenous administration, but oral clearance of midazolam was not altered in rats	Due to inhibition of CYP3A in liver, not in intestine	[77]
	Ginseng berry extract (p.o.)	Ginseng berry extract did not affect the PK properties of intravenous administered nifedipine or cyclosporin, but markedly increased the absolute bioavailability of both drugs after oral administration in rats	Due to inhibition of CYP3A in intestine, not in liver	[77]
	Schisandra chinensis fruit (p.o.)	S. chinensis fruit extract increased AUC and Cmax of orally administered midazolam, but there was no little change in the PK properties of intravenously administered midazolam in rats	Due to intensive inhibitory effect on CYP3A in intestine, not in liver	[64]
Dose	Andrographis paniculata extract (p.o.)	Low dose of Andrographis Herba extract increases theophylline elimination, whereas high-dose of A. paniculata extract decreases theophylline elimination	Due to induction of CYP1A2 by low-dose treatment of A. paniculata extract, but inhibition of CYP1A2 by its high-dose treatment	[72]
	Tinospora cordifolia aqueous-alcoholic extract (p.o.)	High-dose of T. cordifolia aqueous-alcoholic extract, not low-dose, reduced the clearance and increased bioavailability of glibenclamide, respectively, in rats	Due to the inhibition of CYP2C9, 2D6 and 3A4 in liver by high-dose of T. cordifolia aqua-alcoholic extract, not low-dose	[73]
Treatment period	S. chinensis fruit extract (p.o.)	Long-term treatment of S. chinensis fruit extract reduced AUC and Cmax of orally administered midazolam, but the AUC and Cmax of orally administered midazolam were increased after single treatment of Schisandrae Chinensis Fructus extract	Due to stronger induction of CYP3A in liver and intestine than inhibition of CYP3A in long-term treatment; Due to stronger inhibition of CYP3A in intestine, not in liver after single treatment	[72]
	G. biloba leaf extract (p.o.)	Single treatment of G. biloba leaf extract increased the intravenously administered diltiazem concentrations in plasma, but long-term treatment of ginkgo biloba leaf extract reduced the intravenously administered diltiazem concentrations in plasma	Due to inhibition of CYP3A in liver in singe treatment of G. biloba leaf extract; due to induction of CYP3A in liver after long-term treatment	[68,76]
	Lonicera japonica extract (p.o.)	28-day treatment of L. japonica extract increased metformin concentration in liver along with the enhancement of glucose tolerance activity of metformin, but single and 7-day treatment of Lonicera japonica extract did not alter metformin concentration in plasma and liver as well as glucose tolerance activity.	Due to reduction in mate1-mediated biliary excretion of metformin by 28-day treatment of Lonicera japonica extract	[29]
	Houttuynia cordata extract (p.o.)	28-day treatment of H. cordata extract increased metformin concentration in plasma, liver and kidneys along with the enhancement of glucose-lowering effect in rats, but there no change of PK and PD of metformin after single and 7-day treatment of Houttuynia cordata extract	Increase in metformin plasma concentrations due to the decrease in renal oct2-mediated renal excretion of metformin and metformin concentration in kidneys; enhancement of glucose tolerance activity due to the increase in oct1-mediated renal uptake of metformin	[30]