Cardiovascular Therapeutics

Review Article

Pharmacokinetic Interactions between Cardiovascular Medicines and Plant Products

Table 1

Clinically relevant pharmacokinetic plant-cardiovascular drugs interactions.


Cardiovascular medicines	Plant	Plant product	Dosage, Duration of administration	Plant bioactivity	Bioactive phytochemicals	Interaction	Putative mechanism	Ref.

Calcium channel blockers

Felodipine	Citrus × paradisi	Grapefruit juice with 450 μg naringin/mL (Old South grapefruit juice- Lykes Pasco Inc, USA)	200 mL, single dose	Cardioprotective Cholesterol-lowering effect Chemopreventive	Flavonoids Furanocoumarins	↑AUC, of felodipine ↑antihypertensive effects	↓CYP3A4	[5, 62]
		Frozen juice concentrate (Miracle Mart, Canada)	200 mL (prepared by diluting 50 mL concentrate), single dose					[63]
		Regular-strength grapefruit juice (Everfresh Inc., Canada)	250 mL, single dose					[64]
		Intact grapefruit, Homogenized grapefruit segments Extract of segment-free parts (not available manufacturer)	Not available					[65]
	Mentha piperita, peppermint	Essential oil (not available manufacturer)	600 mg, single dose	Spasmolytic Carminative Antiemetic Expectorant	Menthol, Menthyl acetate	↑AUC, of felodipine	↓CYP3A4	[66, 67]

Nifedipine	Panax ginseng, Korean ginseng	Not available	200 mg/day, 18 days	Adaptogenic	Ginsenosides	↑ of nifedipine (29%)	↓CYP3A4	[68]
	Ginkgo biloba	Not available	120 mg/day, 18 days	Neuroprotective Vascular effects	Ginkgolides Bilobalides Flavonoids	↑ of nifedipine (30%)	Unknown	[68]
	Ginkgo biloba	Ginkgolon-24, standardized extract to over 24% flavonoid glycosides, 6% terpene lactones, less than 1 ppm ginkgolic acids (Tokiwa Phytochemical Co. Ltd., Japan)	240 mg/day, single dose	Neuroprotective Vascular effects	Ginkgolides Bilobalides Flavonoids	↑, adverse reactions of nifedipine (only in some subjects)	Unknown	[26]
	Hypericum perforatum, St. John’s wort	Not available	900 mg/day, 18 days	Antidepressant	Hyperforin Hypericin Flavonoids	↓nifedipine blood concentration	↑CYP3A4	[67, 68]

Nisoldipine	Citrus × paradisi	Grapefruit juice (Everfresh Inc., Canada)	250 mL, single dose	Cardioprotective Cholesterol-lowering effect Chemopreventive	Flavonoids Furanocoumarins	↑bioavailabili ty of nisoldipine (85%)	↓CYP3A4	[5, 69]

Verapamil	Hypericum perforatum	Movina®, Standardized extract to hyperforin 3-6% (Boehringer Ingelheim, Sweden)	300 mg×3/day, 14 days	Antidepressant	Hyperforin Hypericin Flavonoids	↓AUC of R- and S-verapamil (78-80%)	↑CYP3A4	[67, 70]

Cardiac inotropic drugs

Digoxin	Hypericum perforatum	Standardized extract LI 160 to 0.12-0.28% hypericin (Lichtwer Pharma AG, Germany)	900 mg/day, 10 days	Antidepressant	Hyperforin Hypericin Flavonoids	↓ of digoxin (25%) ↓ (33%)	↑P-gp	[70]
		Jarsin 300®, LI 160 extract (Lichtwer Pharma AG, Germany)	900 mg/day, 14 days			↓AUC of digoxin (18%)		[71]
		Standardized extract WS 5572 to 0.12-0.28% hypericin and 3-6% hyperforin (Dr. Willmar Schwabe Pharmaceuticals, Germany)	900 mg/day, 14 days			↓AUC of digoxin (23%)		[72]
		Remotiv, standardized extract ZE 117 to 0.2% hypericin and less than 0.5% hyperforin (Ewopharma, Czech Republic)	500 mg/day, 14 days			No change for AUC of digoxin		[73]
		Esbericum®, standardized extract to 1.47% hyperforin (Schape & Brummer, Germany)	240 mg/day, 11 days			↓AUC of digoxin (3%)		[74]
		Powder (not specified manufacturer)	2000 mg/day, 14 days			No change for AUC of digoxin		[73]
		Powder (not specified manufacturer)	2000 mg/day, 14 days			↓AUC of digoxin (18%)		[73]
		Powder (not specified manufacturer)	4000 mg/day, 14 days			↓AUC of digoxin (27%)		[75]
	Thea sinensis, green tea	Ggreen Tea catechin (Atlantic Essential Products, USA)	630 mg/day, pretreatment (13 days) and concomitant administration	Antioxidant Antiaging Neuroprotective Chemopreventive	Catechins (EC, EGCG)	↓AUC of digoxin (26-28%) ↓Cmax of digoxin (31-33%)	↑P-gp ↓digoxin uptake	[76]

Beta-blockers

Atenolol	Malus pumila, apple	Apple juice (Martinelli’s Gold Medal apple juice, USA)	1.2 L/day, in three phases of study	Antioxidant Anti-inflammatory Cardioprotective Anti-cancer	Flavonoids	↓AUC of atenolol (82%) ↓systemic exposure to atenolol	Unknown (possible mediated by OATP function and modulation of intestinal drug uptake)	[77]

Nadolol	Thea sinensis	Green tea beverage (Healthya, Japan)	700 mL/day, 14 days	CNS Stimulant Antioxidant Antiaging Neuroprotective Chemopreventive	Catechins (EGCG) Methylxanthines	↓ nadolol (85%) ↓ anti hypertensive effect	↓intestinal OATP1A2	[52, 78]

Talinolol	Curcuma longa, turmeric	Curcumin soft capsules (mixture of dimethoxy curcumin and bismethoxy curcumin) (ShenWei Pharmaceutical, China)	300 mg/day, 6 days	Anti-inflammatory Antioxidant Anti-carcinogenic Cholesterol-lowering effect	Curcuminoids	↓AUC, of talinolol	↑P-gp	[79]
	Curcuma longa, turmeric	Curcumin capsules (mixture of dimethoxy curcumin and bismethoxy curcumin) (Avmazon, USA)	1000 mg/day, 14 days		Curcuminoids	↑AUC, of talinolol	↓intestinal P-gp in subjects with ABCB1 C3435T genotype	[18]
	Ginkgo biloba	Standardized extract (Rui Bang Pharmaceutical Company, China)	120 mg ×3/day, 14 days	Neuroprotective Vascular effects	Ginkgolides Bilobalides Flavonoids	↑AUC of talinolol (22-25%), ↑ of talinolol (36%)	↓intestinal P-gp	[16]
	Citrus × paradisi	Regular strength grapefruit juice (712 μmoL/L naringin; 492 μmol/L dihydroxy-bergamottin and 45 μmoL/L bergamottin) (Paradiso- Succo di Pompelmo, Penny GmbH Deutschland, Germany)	300 mL (single dose); 900 mL/day, 6 days	Cardioprotective Cholesterol-lowering effect Chemopreventive	Flavonoids Furanocoumarins	↓AUC, of talinolol (56-65%)	↓OATP	[80]
	Schisandra chinensis	Extract (16.85 mg deoxyschisandrin/tablet) (Oriental Pharmaceutical Company, China)	300 mg×2/day, 14 days	Adaptogenic Hepatoprotective	Lignans Flavonoids	↑AUC (47%) ↑ (51%)	↓P-gp	[16, 67]
	Hypericum perforatum	Jarsin 300®, LI 160 extract (Lichtwer Pharma AG, Germany)	900 mg/day, 12 days	Antidepressant	Hyperforin Hypericin Flavonoids	↓ talinolol concentration ↓AUC (31%)	↑P-gp	[67, 81]

Direct renin inhibitors

Aliskiren	Citrus × paradisi	Normal-strength grapefruit juice (Valio Greipptäysmehu, Finland)	200 mL×3/day, 5 days	Cardioprotective Cholesterol-lowering effect Chemopreventive	Furanocoumarins Flavonoids	↓ (81%) ↓ (61%) ↓t_1/2	↓OATP2B1	[29]
	Citrus × paradisi	Grapefruit juice concentrate (Pfanner, Germany)	300 mL, single dose		Furanocoumarins Flavonoids	↓Cmax (61%) ↓AUC (37%)	↓OATP1A2	[31]
	Citrus × sinensis, sweet orange	Concentrate normal-strength orange juice (Valio Greipptäysmehu, Finland)	200 mL×3/day, 5 days	Anti-inflammatory Cardioprotective Vascular effects Chlolesterol-lowering effect Antioxidant	Flavonoids	↓ (80%) ↓ (62%)	↓OATP2B1	[30]
	Malus pumila, apple	Concentrate normal-strength apple juice (Valio Greipptäysmehu, Finland)	200 mL×3/day, 5 days	Antioxidant Anti-inflammatory Cardioprotective Anti-cancer	Flavonoids	↓ (84%) ↓ (63%)	↓OATP2B1	[30]

ARBs

Losartan	Silybum marianum, milk thistle	Silymarin (Madaus AG, Germany)	140 mg×3/day, 14 days	Hepatoprotective	Flavanolignans	CYP2C9∗1/∗1 ↑ of losartan ↑ losartan ↑ losartan CYP2C9∗1/∗1, CYP2C9∗1/∗3 ↓ of E-3174 ↓ of E-3174 ↓ of E-3174	↓CYP2C9	[36]

Oral anticoagulants

Phenprocoumon	Hypericum perforatum	Jarsin 300®, LI 160 extract (Lichtwer Pharma AG, Germany)	900 mg/day, single dose	Antidepressant	Hyperforin Hypericin Flavonoids	↓ AUC phenpro coumon (17%) ↓anticoagulant effect	↑CYP2C9 ↑CYY3A4	[67, 82]

Warfarin	Hypericum perforatum	Standardized extract equivalent to 1 g aerial parts, 0.825 mg hypericin and 12.5 mg hyperforin/tablet (Bioglan, Australia)	One tablet×3/day, 14 days	Antidepressant	Hyperforin Hypericin Flavonoids	↑warfarin clearance (27%) ↓INR	↑CYP1A2 ↑CYP3A4 ↑CYP2C19	[83, 84]
	Panax ginseng	Standardized extract G115 to ginsenosides 4% (Ginsana, Switzerland)	One capsule×3/day, 14 days	Adaptogenic	Ginsenosides	↓INR ↓anticoagulant effect	↑metabolism of warfarin (possible)	[49, 85, 86]
	Panax ginseng	Extract equivalent to 0.5 g root and 8.93 mg ginsenosides (ginsenoside Rg1)/capsule (Golden Glow, Australia)	2 capsules×3/ day, 7 days	Adaptogenic	Ginsenosides	No statistically significant changes of INR, PT and AUC values	Unknown	[83]
	Panax quinquefolius (American ginseng)	Root powder (Wisconsin Ginseng Board, USA)	1g×3/day, 21 days	Adaptogenic	Triterpenoids	↓INR ↓AUC, of warfarin	Unknown	[67, 86]
	Ginkgo biloba	Tavonin™ – standardized extract EGb 761 (Schwabe Willmar GmbH&Co, Gemany)	2 tablets×3/day, 7 days	Neuroprotective Vascular effects	Bilobalid Ginkgolides Flavonoids	No effect on apparent clearance of warfarin enantiomers No effect on clotting status		[87]
	Ginkgo biloba	Various products based on Ginkgo biloba leaf extract (not specified manufacturer)	40 mg×3/day, 18 months; 40 mg×3-4/day, 6 months	Neuroprotective Vascular effects	Bilobalid Ginkgolides Flavonoids	↑effect of warfarin, bleeding effects	↓CYP2C9/C19, ↓CYP3A4 ↓CYP1A2	[88–91]
	Thea sinensis	Green tea beverage (not specified manufacturer)	0,5-1 gallon/day, 7 days	CNS Stimulant Antiaging Antioxidant Chemopreventive Neuroprotective	Catechins (EGCG) Methylxanthines	↓INR (3.79 vs. 1.37)	Unclear	[52, 92]
	Citrus × paradisi	Ready-to-drink grapefruit juice (President’s Choice, Sunfresh Ltd, Canada)	1.5 L/day, 10 days	Cardioprotective Cholesterol-lowering effect Chemopreventive	Flavonoids Furanocoumarins	↑INR ↑effect of warfarin	↓CYP2C9, CYP3A4	[45, 93]
	Citrus × paradisi	Whole fruit (not specified manufacturer)	One fruit/day, 3 days		Flavonoids Furanocoumarins	↑INR ↑effect of warfarin	↓CYP2C9, CYP3A4	[51]
	Glycine max (soybean)	Soy milk (not available manufacturer)	480 mL/day, 4 weeks	Phytoestrogenic	Isoflavonoids	↓INR ↓effect warfarin	alterations of P-gp/OATP transporters ↓CYP2C9, CYP3A4	[45, 94]
	Salvia miltiorrhiza (Danshen)	Decoction	Dosage is not stated, 2 weeks	Antiplatelet	Tanshinone diterpenes	↑INR ↑effect of warfarin	↓ protein binding of warfarin ↑CYP1A2, CYP3A4	[45, 95]
	Salvia miltiorrhiza (Danshen)	Herbal product (not specified manufacturer)	One month	Antiplatelet	Tanshinone diterpenes	↑INR ↑effect of warfarin	↓ protein binding of warfarin ↑CYP1A2, CYP3A4	[50, 96]

Lipid lowering drugs

Atorvastatin	Hypericum perforatum	Movina®, Standardized extract to hyperforin 3-6% (Boehringer Ingelheim, Sweden)	300 mg×2/day, 28 days	Antidepressant	Hyperforin Hypericin Flavonoids	↓ , AUC ↓ atorvastatin efficiency	↑CYP3A4 ↑P-gp	[67, 97]
	Citrus × paradisi	Double strength grapefruit juice (Minute Maid frozen concentrated grapefruit juice, Coca Cola Foods, USA)	200 mL×3/day, 5 days	Cardioprotective Cholesterol-lowering effect Chemopreventive	Flavonoids Furanocoumarins	↑ (×2.6) ↑ (×3.3)	↓intestinal CYP3A4	[98]
	Citrus × paradisi	Florida grapefruit juice (not specified manufacturer)	300 mL/day, 90 days		Flavonoids Furanocoumarins	↑serum levels of atorvastatin (19-26%) No adverse liver/muscle effects	↓intestinal CYP3A4	[99]

Lovastatin	Citrus × paradisi	Double strength grapefruit juice (not available manufacturer)	200 mL×3/day, 3 days			↑ (×12) ↑ (×15)	↓intestinal CYP3A4	[100]

Pravastatin	Hypericum perforatum	TruNature®, Standardized extract to hypericin 0.3% (Leiner Health Products, USA)	300 mg×3/day, 14 days	Antidepressant	Hyperforin Hypericin Flavonoids	No significant effect on plasma concentrations	-	[101]

Rosuvastatin	EGCG (Thea sinensis)	Teavigo™ (Healthy Origin, USA)	300 mg/day, 12 days	CNS Stimulant Antiaging Antioxidant Chemopreventive Neuroprotective	Catechins	↓exposure to rosuvastatin (19%) at single dose of EGCG	↓intestinal OATP1A2/ OATB2P1	[57]
Rosuvastatin	Hypericum perforatum	Herbal supplement with 300 mg St. John’s wort/capsule (not specified manufacturer)	2 capsules/day	Antidepressant	Hyperforin Hypericin Flavonoids	↓ rosuvastatin efficiency	↑P-gp	[67, 102]

Simvastatin	Hypericum perforatum	TruNature®, Standardized extract to hypericin 0.3% (Leiner Health Products, USA)	300 mg×3/day, 14 days	Antidepressant	Hyperforin Hypericin Flavonoids	↓AUC simvastatin ↓ simvastatin	↑CYP3A4 ↑P-gp	[101]
	Hypericum perforatum	Movina®, Standardized extract to hyperforin 3-6% (Boehringer Ingelheim, Sweden)	300 mg×3/day, 28 days	Antidepressant	Hyperforin Hypericin Flavonoids	↑LDLc ↓ simvastatin efficiency		[103]
	Citrus × paradisi	Double strength grapefruit juice (Minute Maid frozen concentrated grapefruit juice, Coca Cola Foods, USA)	200 mL×3/day, 3 days	Cardioprotective Cholesterol-lowering effect Chemopreventive	Flavonoids Furanocoumarins	↑ simvastatin (×16) ↑ simvastatin (×9)	↓intestinal CYP3A4	[5, 104]
		Normal-strength (Valio Ltd., Finland)	200 mL/day, 3 days			↑ (×3.6) ↑Cmax (3.9)		[105]
		Standard grapefruit juice (Morinaga, Japan)	200 mL×2/day, 2 days			↑AUC of simvastatin (×1.7)		[106]

AUC, area under the concentration-time curve; , maximum plasma concentration; EC, epicatechin; EGCG, epigallocatechin 3-gallate; INR, international normalized ratio; LDLc, low-density lipoprotein (LDL) cholesterol; PT, prothrombin time.