Salvia miltiorrhiza Roots against Cardiovascular Disease: Consideration of Herb-Drug Interactions

Table 1

Inhibitory effects of Danshen extract and its bioactive constituents towards enzyme and transporter activities.

Extract/constituent	Enzyme/transporter	Substrate	(μM)			Reference
			HLMs	Purified	Inhibition type
Tanshinone I	CYP1A1	7-Ethoxyresorufin				[39]
	CYP1A2	7-Ethoxyresorufin				[39]
	CYP1A2	Phenacetin	0.48–2.16	0.11	com	[36, 37]
	CYP2C9	Tolbutamide	51.2	73.4	com	[36]
		Diclofenac	>20			[37]
	CYP2D6	Dextromethorphan	12			[37]
	CYP2E1	Chlorzoxazone	3.67	ND	non	[36]
	CYP3A4	Testosterone	86.9	92.5	com	[36]
		Testosterone	>20			[37]
		Midazolam	>20			[37]
	CE1	o-Nitrophenyl acetate		26.3		[44]
	CE2	o-Nitrophenyl acetate		14.6		[44]
		Irinotecan		1.4		[44]
	P-gp	Digoxin	(Caco-2 cells)			[60]
Tanshinone IIA	CYP1A	7-Ethoxyresorufin				[39]
	CYP1A	7-Methoxyresorufin				[39]
	CYP1A1	7-Ethoxyresorufin				[39]
	CYP1A2	7-Ethoxyresorufin				[39]
	CYP1A2	Phenacetin	1.0–1.45	0.05	com	[36, 37]
	CYP2C9	Diclofenac	>20			[37]
	CYP2C9	Tolbutamide	61.6	88.6	com	[36]
	CYP2D6	Dextromethorphan	>20			[37]
	CYP2E1	Chlorzoxazone	—	—		[36]
	CYP3A4	Midazolam	>20			[37]
		Testosterone	>20			[37]
		Testosterone	219	141	com	[36]
	CE1	o-Nitrophenyl acetate		6.9		[44]
	CE2	o-Nitrophenyl acetate		2.5		[44]
		Irinotecan		0.07		[44]
Cryptotanshinone	CYP1A1	7-Ethoxyresorufin				[39]
	CYP1A2	7-Ethoxyresorufin				[39]
	CYP1A2	Phenacetin			com	[38]
		Phenacetin	0.45–1.88	0.27	com	[36, 37]
	CYP2C9	Diclofenac	8		mixed	[37]
		Tolbutamide	22.9	9.90	com	[36]
	CYP2D6	Dextromethorphan	68		mixed	[37]
	CYP2E1	Chlorzoxazone	10.87	ND	com	[36]
	CYP3A4	Midazolam	>20			[37]
		Testosterone	>20			[37]
		Testosterone	120	59.9	com	[36]
	CE1	o-Nitrophenyl acetate		0.54		[44]
	CE2	o-Nitrophenyl acetate		0.14		[44]
		Irinotecan		0.29		[44]
Dihydrotanshinone I	CYP1A2	Phenacetin	0.53	0.02	com	[36]
	CYP2C9	Tolbutamide	1.92	3.14	com	[36]
	CYP2E1	Chlorzoxazone	—	ND	un	[36]
	CYP3A4	Testosterone	2.11	2.98	non	[36]
		Midazolam				[33]
	CE1	o-Nitrophenyl acetate		0.40		[44]
	CE2	o-Nitrophenyl acetate		0.12		[44]
	CE2	Irinotecan		1.83		[44]
Miltirone	CE1	o-Nitrophenyl acetate		2.53		[44]
	CE2	o-Nitrophenyl acetate		0.04		[44]
	CE2	Irinotecan		0.08		[44]
Tanshinone IIA sulfonate	CYP2A6	Coumarin	>10			[31]
	CYP2C9	Tolbutamide	>10
	CYP2C19	s-mephenytoin	>10
	CYP2D6,	Metoprolol	>10
	CYP2E1	Chlorzoxazone	>10
	CYP3A4	Midazolam	3.2		com
	CE1	o-Nitrophenyl acetate		>100		[44]
	CE2	o-Nitrophenyl acetate		3.9
	CE2	Irinotecan		28.8
Tanshinol	CYP1A2	Phenacetin				[37]
	CYP2C9	Diclofenac	35		com
	CYP2D6	Dextromethorphan	>20
	CYP3A4	Midazolam	>20
		Testosterone	>20
	OAT1	p-Aminohippuric acid		40.4		[54]
						[56]
	OAT2	Prostaglandin F2α				[56]
	OAT3	Estrone sulfate		8.6		[54]
						[56]
	OAT4	Estrone sulfate				[56]
Protocatechuic aldehyde	CYP1A2	Phenacetin	>20			[37]
	CYP2C9	Diclofenac	>20
	CYP2D6	Dextromethorphan	>20
	CYP3A4	Midazolam
		Testosterone
Protocatechuic acid	CYP1A2	Phenacetin	>20			[37]
	CYP2C9	Diclofenac	>20
	CYP2D6	Dextromethorphan	>20
	CYP3A4	Midazolam	>20
		Testosterone	>20
Salvianolic acid B	CYP1A2	Phenacetin				[37]
	CYP2C9	Diclofenac	>20
	CYP2D6	Dextromethorphan	>20
	CYP3A4	Midazolam	>20
		Testosterone	>20
	OAT1	p-Aminohippuric acid		22.2		[54]
	OAT3	Estrone sulfate		19.8
Salvianolic acid A	OAT1	p-Aminohippuric acid		5.6		[54]
	OAT3	Estrone sulfate		0.16
Lithospermic acid	OAT1	p-Aminohippuric acid		20.8		[54]
	OAT3	Estrone sulfate		0.59
Rosmarinic acid	OAT1	p-Aminohippuric acid		0.35		[54]
	OAT3	Estrone sulfate		0.55
Danshen	CYP1A2	Phenacetin				[64]
Danshen	CYP3A4	Testosterone			com	[35]
Danshen ethanol	CYP1A2	Phenacetin			com	[34]
	CYP3A4	Testosterone			com
Danshen ethanol	CYP3A4	Midazolam				[33]
	CYP1A2,	Phenacetin	>10			[32]
	CYP2A6	Coumarin	>10
	CYP2C9	Tolbutamide	>10
	CYP2C19	s-mephenytoin	>10
	CYP2D6,	Metoprolol	>10
	CYP2E1	Chlorzoxazone	>10
	CYP3A4	Midazolam			non

com, competitive; non, noncompetitive; un, uncompetitive.
, IC50 (μM).
#, μg/mL.
tanshinol 3.1, salvianolic acid B 37.3, rosmarinic acid 1.8 and protocatechuic aldehyde 0.16 mg/g, and dihydrotanshinone I 12.7, cryptotanshinone 34.6, tanshinone I 10.4, and tanshinone IIA 22.6 μg/g.
tanshinol 31, salvianolic acid B 41, rosmarinic acid 6.1, and protocatechuic aldehyde 2.8 mg/g, dihydrotanshinone I 98, cryptotanshinone 70, tanshinone I 32, and tanshinone IIA 21 μg/g.
tanshinol 2.68, salvianolic acid B 209, rosmarinic acid 14.9, and protocatechuic aldehyde 0.64, dihydrotanshinone I 9.3, cryptotanshinone 36.8, tanshinone I 17.9, and tanshinone IIA 118 mg/g.
tanshinone IIA 106.2, cryptotanshinone 88.0, tanshinone I 53.1, and dihydrotanshinone I 13.5 mg/g.
salvianolic acid B (≥85%), rosmarinic acid (≥10.1%), and lithospermic acid (≥1.9%).