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Safety of St John's wort (Hypericum perforatum)

2000; Elsevier BV; Volume: 355; Issue: 9203 Linguagem: Inglês

10.1016/s0140-6736(05)73227-x

1474-547X

Qun‐Ying Yue, Carin Bergquist, Barbro Gerdén,

Pharmacogenetics and Drug Metabolism

In Sweden, products containing extracts of St John's wort1Ernst E Second thoughts about safety of St John's wort.Lancet. 1999; 354: 2014-2016Summary Full Text Full Text PDF PubMed Scopus (288) Google Scholar are marketed as natural remedies and not as food supplements and the Medical Products Agency (MPA) is responsible for the approval of these products. St John's wort is contained as the sole ingredient or in combination with other active ingredients in several products approved in Sweden as natural remedies. Slight mood lowering has been deemed an appropriate indication for self-medication which is a prerequisite for natural remedies.Since 1998 the MPA has received seven case reports of a reduced anticoagulant effect of warfarin—ie, a decreased International Normalised Ratio (INR)—associated with concomitant use of St John's wort (table). Most patients were stable on warfarin for some time before St John's wort was started. Although none of the patients developed thromboembolic complications, the decrease in INR was thought to be clinically significant. The INR returned to target values either after the warfarin dose was increased or St John's wort was withdrawn. The reduced effect of warfarin suggests an induction of cytochrome P450 2C9.2Kaminsky LS Zhang ZY Human P450 metabolism of warfarin.Pharmacol Ther. 1997; 73: 67-74Crossref PubMed Scopus (686) Google ScholarTable 1Seven cases of decreased effect of warfarin during concomitant treatment with St John's wortPatientsINR beforeINR duringDuration of warfarin treatmentWarfarin dose once St John's wort treatment started79 years, female2·5–3·81·72·5 yearsIncreased from 18·5 to 21·25 mg/week65 years, male2·4–3·62·0–2·14 yearsIncreased from 37·5 to 40 mg/week. INR returned to 2·7 on the ordinary dose of 37·5mg/week once St John's wort was stopped.76 years, male2·31·110 daysIncreased.61 years, femaleNA1·2Years.INR decreased and then increased after St John's wort was stopped.84 years, female2·9–3·61·5Stable ≥6 months.Stable for ≥6 months. INR returned to target range once St John's wort stopped.56 years, female2·61·5Unknown.INR returned to previous value after St John's wort stopped.85 years, male2·1–4·11·5Long time.INR decreased so dose increased while St John's wort was continued.NA=not available. Open table in a new tab In addition, the MPA has received eight reports of intermenstrual bleedings and one report of changed menstrual bleeding from manufacturers of St John's wort products. Most reports concerned women aged 23–31 years who had been on oral contraceptives for a long time. Time between starting St John's wort and onset of menstrual disorders varied, and was about 1 week in five of the patients. There was recovery after St John's wort was stopped in three patients, for whom outcome was known. This suggests an induction of CYP3A4, which is involved in the metabolism of steroids. Decreased steroid concentrations and breakthrough bleedings have been reported when oral contraceptives are combined with known enzme inducers.3LeBel M Masson E Guilbert E et al.Effects of rifabutin and rifampicin on the pharmacokinetics of ethinylestradiol and norethindrone.J Clin Pharmacol. 1999; 38: 1042-1050Crossref Scopus (60) Google Scholar Induction of CYP3A4 by St John's wort is also supported by pharmacokinetic data. Kerb and colleagues4Kerb R Bauer S Brockmöller J Roots I Urinary 6-β-hydroxycortisol excretion rate is affected by treatment with hypericum extract.Eur J Clin Pharmacol. 1997; 52 (abstr): A186Google Scholar found an increased 6-β-hydroxycortisol excretion after repeated doses of St John's wort and in a study on dextromethorphan presented at the New Clinical Drug Evaluation (NCDEV), 39th Annual Meeting, 1999, June 1–4, Boca Raton, Florida, USA, CYP3A4 activity was found to increase when patients were also taking St John's wort. It is worth pointing out that these are in-vivo and not in-vitro studies, as stated in the commentary by E Ernst.1Ernst E Second thoughts about safety of St John's wort.Lancet. 1999; 354: 2014-2016Summary Full Text Full Text PDF PubMed Scopus (288) Google ScholarThe reported cases of interactions together with pharmacokinetic data provide a strong indication that St John's wort is an inducer of a broad range of drug-metabolising enzymes. The study by Johne and colleagues, which shows decreased concentrations of digoxin, suggests that St John's wort might also induce the transport protein P-glycoprotein.5Johne A Brockmöller J Bauer S Maurer A Langheinrich M Roots I Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort.(Hypericum perforatum). Clin Pharmacol Ther. 1999; 66: 338-345Crossref PubMed Scopus (558) Google ScholarThe MPA has contacted the companies marketing St John's wort products in Sweden and requested studies on the extent and implications of drug-drug interactions. In the meantime, the companies have been requested to add on the packaging and patient information leaflet that St John's wort products should not be used concomitantly with any medicinal product. In Sweden, products containing extracts of St John's wort1Ernst E Second thoughts about safety of St John's wort.Lancet. 1999; 354: 2014-2016Summary Full Text Full Text PDF PubMed Scopus (288) Google Scholar are marketed as natural remedies and not as food supplements and the Medical Products Agency (MPA) is responsible for the approval of these products. St John's wort is contained as the sole ingredient or in combination with other active ingredients in several products approved in Sweden as natural remedies. Slight mood lowering has been deemed an appropriate indication for self-medication which is a prerequisite for natural remedies. Since 1998 the MPA has received seven case reports of a reduced anticoagulant effect of warfarin—ie, a decreased International Normalised Ratio (INR)—associated with concomitant use of St John's wort (table). Most patients were stable on warfarin for some time before St John's wort was started. Although none of the patients developed thromboembolic complications, the decrease in INR was thought to be clinically significant. The INR returned to target values either after the warfarin dose was increased or St John's wort was withdrawn. The reduced effect of warfarin suggests an induction of cytochrome P450 2C9.2Kaminsky LS Zhang ZY Human P450 metabolism of warfarin.Pharmacol Ther. 1997; 73: 67-74Crossref PubMed Scopus (686) Google Scholar NA=not available. In addition, the MPA has received eight reports of intermenstrual bleedings and one report of changed menstrual bleeding from manufacturers of St John's wort products. Most reports concerned women aged 23–31 years who had been on oral contraceptives for a long time. Time between starting St John's wort and onset of menstrual disorders varied, and was about 1 week in five of the patients. There was recovery after St John's wort was stopped in three patients, for whom outcome was known. This suggests an induction of CYP3A4, which is involved in the metabolism of steroids. Decreased steroid concentrations and breakthrough bleedings have been reported when oral contraceptives are combined with known enzme inducers.3LeBel M Masson E Guilbert E et al.Effects of rifabutin and rifampicin on the pharmacokinetics of ethinylestradiol and norethindrone.J Clin Pharmacol. 1999; 38: 1042-1050Crossref Scopus (60) Google Scholar Induction of CYP3A4 by St John's wort is also supported by pharmacokinetic data. Kerb and colleagues4Kerb R Bauer S Brockmöller J Roots I Urinary 6-β-hydroxycortisol excretion rate is affected by treatment with hypericum extract.Eur J Clin Pharmacol. 1997; 52 (abstr): A186Google Scholar found an increased 6-β-hydroxycortisol excretion after repeated doses of St John's wort and in a study on dextromethorphan presented at the New Clinical Drug Evaluation (NCDEV), 39th Annual Meeting, 1999, June 1–4, Boca Raton, Florida, USA, CYP3A4 activity was found to increase when patients were also taking St John's wort. It is worth pointing out that these are in-vivo and not in-vitro studies, as stated in the commentary by E Ernst.1Ernst E Second thoughts about safety of St John's wort.Lancet. 1999; 354: 2014-2016Summary Full Text Full Text PDF PubMed Scopus (288) Google Scholar The reported cases of interactions together with pharmacokinetic data provide a strong indication that St John's wort is an inducer of a broad range of drug-metabolising enzymes. The study by Johne and colleagues, which shows decreased concentrations of digoxin, suggests that St John's wort might also induce the transport protein P-glycoprotein.5Johne A Brockmöller J Bauer S Maurer A Langheinrich M Roots I Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort.(Hypericum perforatum). Clin Pharmacol Ther. 1999; 66: 338-345Crossref PubMed Scopus (558) Google Scholar The MPA has contacted the companies marketing St John's wort products in Sweden and requested studies on the extent and implications of drug-drug interactions. In the meantime, the companies have been requested to add on the packaging and patient information leaflet that St John's wort products should not be used concomitantly with any medicinal product.