St John’s wort

• St John’s wort is known to interact with many conventional drugs because of its ability to induce the activity of CYP3A4 and P-glycoprotein, which are involved in the metabolism and distribution of the majority of drugs.

• CYP2C19, CYP2C8 and CYP2E1 may also be induced by St John’s wort, although the evidence is not conclusive and further study is needed.

• In general, CYP2C9 and CYP1A2 do not appear to be significantly affected by St John’s wort; however, isolated reports of an interaction have still occurred.

• Hyperforin is the active constituent believed to be central to the inducing effects of St John’s wort.

• As St John’s wort preparations and dose regimens are varied, the amount of hyperforin exposure will also vary a great deal, which makes predicting whether an interaction will occur, and to what extent, difficult.

St John’s wort + 5-Aminolevulinic acid

An isolated case report describes a severe phototoxic reaction attributed to a synergistic effect of 5-aminolevulinic acid and St John’s wort.

Mechanism

It was suggested that there was a synergistic photosensitivity reaction between the two drugs. Importance and management This appears to be the only report of such an effect, but bear it in mind in the event of an unexpected adverse reaction to 5-aminolevulinic acid.

St John’s wort + Benzodiazepines

Long-term use of St John’s wort decreases the plasma levels of alprazolam, midazolam and quazepam. St John’s wort preparations taken as a single dose, or containing low-hyperforin levels, appear to have less of an effect.

Mechanism

Alprazolam, midazolam and quazepam are substrates of the cytochrome P450 isoenzyme CYP3A4. St John’s wort appears to induce CYP3A4, thus increasing the metabolism of oral midazolam, alprazolam and quazepam, and reducing the bioavailability of these benzodiazepines. Hyperforin appears to be the main active constituent that induces CYP3A4, because high-hyperforin extracts have more of an inducing effect than low-hyperforin extracts.

St John’s wort + Caffeine

Two studies suggest that St John’s wort increases the metabolism of caffeine. However, four other studies using preparations of varying hyperforin content suggest that the metabolism of caffeine is not affected by St John’s wort.

Mechanism

These studies investigated whether St John’s wort had any effect on the cytochrome P450 isoenzyme CYP1A2 by which caffeine is metabolised.

Importance and management

The extent of any interaction with caffeine may depend on the St John’s wort preparation involved and dose used and may be correlated with the dose of hyperforin.

However, these studies generally suggest that an interaction between St John’s wort and caffeine is unlikely to be clinically important.

Caffeine is often used as a probe drug for CYP1A2 activity, and therefore these results also suggest that a significant pharmacokinetic interaction as a result of this mechanism between St John’s wort and other CYP1A2 substrates is unlikely.

St John’s wort + Calcium-channel blockers

St John’s wort significantly reduces the bioavailability of nifedipine and verapamil. Other calcium-channel blockers would be expected to interact similarly.

Mechanism

It appears that St John’s wort decreased the bioavailability of both nifedipine and verapamil by inducing their metabolism by the cytochrome P450 isoenzyme CYP3A4 in the gut. An effect on Pglycoprotein- mediated transport is not likely, as intestinal permeability was not significantly altered.

St John’s wort + Digoxin

Digoxin toxicity occurred in a patient taking digoxin when he stopped taking St John’s wort. There is good evidence that some preparations of St John’s wort can reduce the levels of digoxin by about one-quarter to one-third.

Mechanism

St John’s wort, and specifically hyperforin, a major active constituent, has been shown to increase the activity of the P-glycoprotein drug transporter protein in the intestines, which reduces the absorption of digoxin.

St John’s wort + Imatinib

St John’s wort lowers serum imatinib levels.

Mechanism

St John’s wort induces intestinal CYP3A4 and it therefore also reduces imatinib levels.

St John’s wort + Proton pump inhibitors

St John’s wort induces the metabolism of omeprazole, and this might result in reduced efficacy. Other proton pump inhibitors are likely to be similarly affected.

Mechanism

St John’s wort increases the metabolism of omeprazole by inducing both CYP2C19 and CYP3A4.1

St John’s wort + Tricyclic antidepressants

The plasma levels of amitriptyline and its active metabolite, nortriptyline, are modestly reduced by St John’s wort.

Mechanism

Not fully understood. St John’s wort is known to induce the activity of the cytochrome P450 isoenzyme CYP3A4, which is a minor route of metabolism of the tricyclic antidepressants.

However, the tricyclics are predominantly metabolised by CYP2D6, so an effect on CYP3A4 is unlikely to lead to a clinically relevant reduction in their levels.

Induction of P-glycoprotein by St John’s wort may also contribute; however, the extent of its involvement in the transport of the tricyclics is unclear.

Reference

Wurglics M, Schubert-Zsilavecz M. Hypericum perforatum: a ‘modern’ herbal antidepressant: pharmacokinetics of active ingredients. Clin Pharmacokinet (2006) 45, 449–68.

Xie H-G, Kim RB. St John’s wort-associated drug interactions: Short-term inhibition and long-term induction? Clin Pharmacol Ther (2005) 78, 19–24.

Imai H, Kotegawa T, Tsutsumi K, Morimoto T, Eshima N, Nakano S, Ohashi K. The recovery time-course of CYP3A after induction by St John’s wort administration. Br J Clin Pharmacol (2008) 65, 701–7.

Bauer S, Stormer E, Johne A, Kruger H, Budde K, Neumayer H-H, Roots I, Mai I. Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John’s wort in renal transplant patients. Br J Clin Pharmacol (2003) 55, 203–11.

Hennessey M, Kelleher D, Spiers JP, Barry M, Kavanagh P, Back D, Mulcahy F, Feely J. St John’s Wort increases expression of P-glycoprotein: Implications for drug interactions. Br J Clin Pharmacol (2002) 53, 75–82.

Ladner DP, Klein SD, Steiner RA, Walt H. Synergistic toxicity of delta-aminolaevulinic acid-induced protoporphyrin IX used for photodiagnosis and hypericum extract, a herbal antidepressant. Br J Dermatol (2001) 144, 901–22.

Markowitz JS, Donovan JL, DeVane CL, Taylor RM, Ruan Y, Wang J-S, Chavin KD. Effect of St John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA (2003) 290, 1500–4.

Markowitz JS, DeVane CL, Boulton DW, Carson SW, Nahas Z, Risch SC. Effect of St John’s wort (Hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers. Life Sci (2000) 66, 133–9.

Frye RF, Fitzgerald SM, Lagattuta TF, Hruska MW, Egorin MJ. Effect of St John’s wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther (2004) 76, 323–9.

Smith P. The influence of St John’s wort on the pharmacokinetics and protein binding of imatinib mesylate. Pharmacotherapy (2004) 24, 1508–14.

Wang LS, Zhou G, Zhu B, Wu J, Wang JG, Abd El-Aty AM, Li T, Liu J, Yang TL, Wang D, Zhong XY, Zhou HH. St John’s wort induces both cytochrome P450 3A4- catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole. Clin Pharmacol Ther (2004) 75, 191–7.

Johne A, Schmider J, Brockmoller J, Stadelmann AM, Stormer E, Bauer S, Scholler G, Langheinrich M, Roots I. Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John’s wort (Hypericum perforatum). J Clin Psychopharmacol (2002) 22, 46–54.