Table 4. Drug interactions of Hyperici herba.

ATC therapeutic subgroup	ATC pharmacological/chemical subgroup	Drugs	Pharmacokinetic basis of interaction	Pharmacodynamic basis of interaction	Manifestation of interaction
Drugs for acid related disorders (A02)	Proton pump inhibitors	Omeprazole	CYP2C19 CYP3A4		↓ plasma level	Borrelli & Izzo (2009)
Antithrombotic agents (B01)	Platelet aggregation inhibitors excl. heparin	Clopidogrel	CYP1A2 CYP2D6		↑ active metabolites plasma level ↑ antithrombotic effect ! adverse reaction (bleeding)	Lau et al. (2011)
	Vitamin K antagonists	Warfarin Phenprocoumon	CYP1A2 CYP2C9 CYP3A4 CYP2C19		↓ INR ↑ PT ↓ anticoagulant effect	Borrelli & Izzo (2009)
Cardiac therapy (C01)	Cardiac glycosides	Digoxin	CYP3A4 Pgp		↓ plasma level	Borrelli & Izzo (2009)
Antihypertensives (C02)	Antiadrenergic agents, centrally acting (Rauvolfia alkaloids)	Reserpine	CYP1A2 CYP2C6 CYP2D1 CYP2D2 CYP2E1 CYP3A4	Hypericum is a serotonin reuptake and MAO inhibitor.	antagonistic effect	Nicolussi et al. (2020)
Calcium channel blockers (C08)	Selective calcium channel blockers with direct cardiac effects	Verapamil	CYP3A4 CYP1A2		↓ plasma level	Tannergren et al. (2004)
Lipid modifying agents (C10)	HMG CoA reductase inhibitors	Simvastatin Pravastatin Fluvastatin Atorvastatin Lovastatin	CYP3A4 P-gp		↓ plasma level	Eggertsen, Andreasson & Andrén (2007)
Sex hormones and modulators of the genital system (G03)	Hormonal contraceptives for systemic use	Ethinylestradiol (EE), Estradiol + Progestogens	CYP1A2 CYP2C9 CYP3A4		↓ estrogen (EE) plasma level (13–15%) ! breakthrough bleeding ! contraceptive failure ! alternate methods of contraception are advised.	Borrelli & Izzo (2009), Hall et al. (2003)
Urologicals (G04)	Testosterone-5α reductase inhibitors	Finasteride	CYP3A4 P-gp		↓ plasma level	Lundahl et al. (2009)
Antivirals for systemic use (J05)	Protease inhibitors	Amprenavir Indinavir Nelfinavir Ritonavir Saquinavir	CYP3A4 P-gp		↓ plasma level ↓ AUC (57%) ↑ elimination	Borrelli & Izzo (2009), James (2000)
	Non-nucleoside reverse-transcriptase inhibitors	Nevirapine Delavirdine Efavirenz	CYP3A4 P-gp		↓ plasma level	Borrelli & Izzo (2009)
Antineoplastic agents (L01)	BCR-ABL tyrosine kinase inhibitors	Imatinib	CYP3A4		↓ plasma level	Smith et al. (2004)
	Topoisomerase 1 inhibitors	Irinotecan	CYP3A4		↓ plasma level ↓ AUC (42%)	Mathijssen et al. (2002)
	Sensitizers used in photodynamic/radiation therapy	Aminolevulinic acid	up-regulation of CYP activity	Hypericin is phototoxic.	↑ light-induced toxicity (15%) ! Synergistic photensitivity reaction between aminolevulinic acid and hypericin.	Boiy, Roelandts & de Witte (2011), Ladner et al. (2001), Ritz et al. (2012), Schneider-Yin et al. (2009)
Endocrine therapy (L02)	Anti-estrogens	Tamoxifen	CYP2C9		↓ plasma level	Hansten (2018)
Immunosuppressants drugs (L04)	Calcineurin inhibitors	Cyclosporine Tacrolimus	CYP3A4 P-gp		↓ cyclosporine (30–70%), and tacrolimus plasma level ! transplant rejection risk	Alscher & Klotz (2003), Borrelli & Izzo (2009), Hebert et al. (2004)
Analgesics (N02)	Opioids, benzomorphan derivatives	Pentazocine	CYP3A4	Hypericum is a serotonin reuptake and MAO inhibitor, GABA agonist	additive serotonergic effect ! risk: serotonin syndrome or Call-Fleming syndrome	Drugs (2023)
	Other opioids	Tramadol	CYP1A2 CYP3A4	Hypericum is a serotonin reuptake and MAO inhibitor, GABA agonist.	additive serotonergic effect ! risk: serotonin syndrome or Call-Fleming syndrome	Sansone & Sansone (2009)
	Drugs used in opioid dependence Opioids, diphenylpropylamine derivatives	Methadone	CYP3A4 CYP2C19 CYP2D6	Hypericum is a serotonin reuptake and MAO inhibitor, GABA agonist.	↑ methadone effect ↑ adverse reactions ! coma risk	Borrelli & Izzo (2009)
	Other analgesics and antipyretics, anilides	Paracetamol	CYP1A2 CYP3A4 CYP2E1		↑ analgetic effect	Jiang et al. (2022)
	Antimigraine preparations, selective serotonin (5-HT1) agonists	Frovatriptan Naratriptan Rizatriptan Sumatriptan Zomitriptan	CYP1A2 CYP3A4 CYP2D6 MAO-A P-gp	Hypericum is a serotonin reuptake and MAO inhibitor, GABA agonist.	additive serotonergic effect ! risk: serotonin syndrome or Call-Fleming syndrome	Bonetto et al. (2007)
Antiepileptics (N03)	Antiepileptics, barbiturates and derivatives	Phenobarbital Pentobarbital Secobarbital	CYP2C9		↓ anticonvulsive effect ! dosage adjustment	Nicolussi et al. (2020)
	Antiepileptics, hydantoin derivatives	Phenytoin	CYP2C9 CYP2C19		↓ anticonvulsive effect ! dosage adjustment	Borrelli & Izzo (2009)
	Antiepileptics, carboxamide derivatives	Carbamazepine	CYP3A4		↓ anticonvulsive effect ! dosage adjustment	Borrelli & Izzo (2009)
Psycholeptics (N05)	Anxiolytics, benzodiazepine derivatives	Alprazolam Diazepam	CYP2C19 CYP3A4		↓ anxiolytic effect	Borrelli & Izzo (2009)
	Hypnotics and sedatives, benzodiazepine derivatives	Midazolam	CYP2C19 CYP3A4		↓ hypnotic effect	Borrelli & Izzo (2009)
Psychoanaleptics (N06)	Antidepressants, non-selective monoamine reuptake inhibitors	Amitriptylin Nortriptylin	CYP3A4 CYP2C9 CYP2D6 P-gp	Hypericum is a serotonin reuptake and MAO inhibitor, GABA agonist.	↓ plasma level of amitriptylin (22%) and its metabolite nortriptylin (42%) ↓ antidepressant effect	Borrelli & Izzo (2009)
	Antidepressants, MAO inhibitors, non-selective	Tranylcypromine	MAO		additive effect ↑ adverse reaction ! 14 days interval	Sacher et al. (2011)
	Antidepressants, selective serotonin reuptake inhibitors	Paroxetine Sertraline	CYP2D6 CYP3A4		additive serotonergic effect ! risk: serotonin syndrome or Call-Fleming syndrome	Cui & Zheng (2016)
	Antidepressants, other antidepressants	Nefazodone	CYP2D6 CYP3A4		additive serotonergic effect ! risk: serotonin syndrome or Call-Fleming syndrome	Borrelli & Izzo (2009)
Drugs for obstructive airway diseases (R03)	Other systemic drugs for obstructive airway diseases, xanthines	Aminophylline Theophylline	CYP1A2		↓ plasma level	Morimoto et al. (2004)
Cough and cold preparations (R05)	Cough suppressants, excl. combinations with expectorants	Dextromethorphan	CYP3A4 CYP2D6	Hypericum is a serotonin reuptake and MAO inhibitor, GABA agonist.	additive serotonergic effect ! risk: serotonin syndrome or Call-Fleming syndrome	Markowitz et al. (2000)
Antihistamines for systemic use (R06)	Other antihistamines for systemic use	Fexofenadine	CYP3A4 P-gp OATP		↑ plasma level ↑ adverse reactions	Wang et al. (2002)

Note:

ATC, Anatomical Therapeutic Chemical Classification System (WHO, 2023); ↑, increase (of); ↓, decrease (of); !, warning; excl., excluding; AUC, area under the curve; GABA, γ-aminobutyric acid; INR, international normalized ratio; MAO, monoamine oxidase; OATP, organic anion transporters; P-gp, P-glycoprotein; PT, prothrombin time.