Hazardous pharmacokinetic interaction of Saint John's wort (Hypericum perforatum) with the immunosuppressant cyclosporin.

Contrary to common belief, over-the-counter herbal remedies may cause clinically relevant drug interactions. With the enclosed report we would like to alert other physicians that herbal extracts of Saint John's wort (Hypericum perforatum) may cause a sudden remarkable decrease of cyclosporin trough concentrations. A kidney transplantation patient treated with 75 mg bid doses of cyclosporin for many years experienced a sudden drop in her cyclosporin trough concentrations. This change was in temporal relationship to hypericum extract comedication, and a re-challenge gave similar results. The mean dose-normalized cyclosporin concentration during this comedication (90% confidence interval) was 0.48 (0.43 to 0.54) ng/(ml x mg) and was constantly below the respective concentration without the herbal remedy (0.84 (0.79 to 0.89) ng/(ml x mg)). This difference in the pharmacokinetics of cyclosporin indicates a relevant influence of St John's wort extract. The potential clinical consequence of this pharmacokinetic herb-drug interaction is apparent, since low cyclosporin levels are associated with an increased risk of rejection after organ transplantation and are usually not suspected upon intake of plant products. In view of the permanently increasing use of St John's wort preparations for various indications and the clinical relevance of this interaction, our report may contribute to the ongoing debate on the prescription status and safety of hypericum extracts.

Critical evaluation of the effect of valerian extract on sleep structure and sleep quality.

A carefully designed study assessed the short-term (single dose) and long-term (14 days with multiple dosage) effects of a valerian extract on both objective and subjective sleep parameters. The investigation was performed as a randomised, double-blind, placebo-controlled, cross-over study. Sixteen patients (4 male, 12 female) with previously established psychophysiological insomnia (ICSD-code 1.A.1.), and with a median age of 49 (range: 22 to 55), were included in the study. The main inclusion criteria were reported primary insomnia according to ICSD criteria, which was confirmed by polysomnographic recording, and the absence of acute diseases. During the study, the patients underwent 8 polysomnographic recordings: i.e., 2 recordings (baseline and study night) at each time point at which the short and long-term effects of placebo and valerian were tested. The target variable of the study was sleep efficiency. Other parameters describing objective sleep structure were the usual features of sleep-stage analysis, based on the rules of Rechtschaffen and Kales (1968), and the arousal index (scored according to ASDA criteria, 1992) as a sleep microstructure parameter. Subjective parameters such as sleep quality, morning feeling, daytime performance, subjectively perceived duration of sleep latency, and sleep period time were assessed by means of questionnaires. After a single dose of valerian, no effects on sleep structure and subjective sleep assessment were observed. After multiple-dose treatment, sleep efficiency showed a significant increase for both the placebo and the valerian condition in comparison with baseline polysomnography. We confirmed significant differences between valerian and placebo for parameters describing slow-wave sleep. In comparison with the placebo, slow-wave sleep latency was reduced after administration of valerian (21.3 vs. 13.5 min respectively, p<0.05). The SWS percentage of time in bed (TIB) was increased after long-term valerian treatment, in comparison to baseline (9.8 vs. 8.1% respectively, p<0.05). At the same time point, a tendency for shorter subjective sleep latency, as well as a higher correlation coefficient between subjective and objective sleep latencies, were observed under valerian treatment. Other improvements in sleep structure - such as an increase in REM percentage and a decrease in NREM1 percentage - took place simultaneously under placebo and valerian treatment. A remarkable finding of the study was the extremely low number of adverse events during the valerian treatment periods (3 vs. 18 in the placebo period). In conclusion, treatment with a herbal extract of radix valerianae demonstrated positive effects on sleep structure and sleep perception of insomnia patients, and can therefore be recommended for the treatment of patients with mild psychophysiological insomnia.

Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum).

OBJECTIVE: Extracts of St John's wort (Hypericum perforatum) are widely used in the treatment of depression, often as an over-the-counter drug. In contrast to its frequent use, knowledge about the pharmacokinetics of ingredients and drug interactions of St John's wort is poor. We studied the interaction between hypericum extract LI160 and digoxin. METHODS: The pharmacokinetics of digoxin were investigated in a single-blind, placebo-controlled parallel study. After the achievement of steady state for digoxin on day 5, healthy volunteers received digoxin (0.25 mg/d) either with placebo (n = 12) or with 900 mg/d LI160 (n = 13) for another 10 days. Digoxin concentration profiles on day 5 were compared with day 6 (single-dose interaction) and day 15 (tenth day of co-medication). RESULTS: There was a highly significant combined-day-and-group effect for digoxin area under the plasma concentration-time curve [AUC(0-24); P = .0001], peak concentration in plasma (Cmax; P = .0001), and plasma drug concentration at the end of a dosing interval (P = .0003) by two-way ANOVA. No statistically significant change was observed after the first dose of hypericum extract [AUC(0-24) at day 6 of 18.1+/-2.9 microg x h/L and 17.7+/-3.0 microg x h/L, mean +/- SD for placebo and hypericum group, respectively]. However, 10 days of treatment with hypericum extract resulted in a decrease of digoxin AUC(0-24) by 25% (day 15, 17.2+/-4.0 microg x h/L and 12.9+/-2.3 microg x h/L; P = .0035). Furthermore, comparison with the parallel placebo group after multiple dosing showed a reduction in trough concentrations and Cmax of 33% (P = .0023) and 26% (P = .0095), respectively. The effect became increasingly pronounced until the tenth day of co-medication. CONCLUSION: As with grapefruit juice, a food product, physicians should also be aware of potential drug-herb interactions. The interaction of St John's wort extract with digoxin kinetics was time dependent. The mechanism involved may be induction of the P-glycoprotein drug transporter.

Urinary 6 beta-hydroxycortisol and D-glucaric acid excretion rates are not affected by lansoprazole treatment.

Lansoprazole has been shown to induce cytochrome P450 1A (CYP1A) and CYP3A enzymes in human hepatocytes in vitro. In this study, urinary excretion of 6 beta-hydroxycortisol (6 beta-OHF) and D-glucaric acid (D-GA) were used to investigate the potential enzyme-inducing property of lansoprazole in vivo. Twenty-four healthy female volunteers (aged 19-35 years), who were taking oral contraceptives containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel, were randomized in a cross-over design for the treatment with either 60 mg lansoprazole or placebo once daily during 2 subsequent menstrual cycles. Urinary excretion rates of 6 beta-OHF and D-GA were measured at days 14 and 21 of the menstrual cycles. Median pretreatment urinary excretion of 6 beta-OHF (212 and 218 micrograms/d, n = 24) and D-GA (20.1 and 32.7 mumol/d) did not significantly differ. Upon treatment median excretion of 6 beta-OHF was 255 and 241 micrograms/d (n = 23), and that of D-GA was 25.5 and 33.8 mumol/d, respectively. Thus, the relatively high dose of 60 mg/d lansoprazole failed to statistically significantly alter urinary excretion of 6 beta-OHF and D-GA, indicating that therapeutic doses of lansoprazole might not exhibit a phenobarbital-like induction in vivo.

Nonlinear kinetics after high-dose omeprazole caused by saturation of genetically variable CYP2C19.

Nonlinear kinetics of omeprazole and its metabolites were investigated after treatment with repeated high doses. Extensive metabolizers relating to cytochrome P450 2C19 (CYP2C19) activity received for 1 week either omeprazole at 40 mg/d (n = 14) or 60 mg/d omeprazole twice daily (n = 8). Five poor metabolizers (PMs) received 40 mg/d for 1 week. Comparison of omeprazole plasma kinetics between extensive metabolizers (EMs) and PMs after 40-mg treatment revealed a dominant role of CYP2C19 over cytochrome P450 3A CYP3A in omeprazole metabolism. Comparing the omeprazole doses of 40 mg and 60 mg in eight EMs on day 7 of treatment showed that CYP2C19-dependent plasma clearance of omeprazole and omeprazole sulfone was reduced from 19.0 to 8.4 L/h (P < .001) and from 19.8 to 9.2 L/h (P = .012), respectively. Similarly, formation half-life of 5'-hydroxyomeprazole increased from 0.58 to 1.45 hours (P = .025) with the higher dose. CYP3A-dependent metabolic routes remained unaffected. Thus, high-dose treatment with omeprazole uncovers saturation kinetics for CYP2C19 pathways in EMs, and CYP3A becomes the predominant enzyme of omeprazole elimination. Moreover, these individuals may be at risk for side effects due to high omeprazole concentrations if high-dose omeprazole treatment is combined with drugs inhibiting CYP3A activity.

Pharmacokinetics of hypericin and pseudohypericin after oral intake of the hypericum perforatum extract LI 160 in healthy volunteers.

The single- and multiple-dose pharmacokinetics of the naphthodianthrones hypericin and pseudohypericin derived from St. John's wort (Hypericum perforatum, LI 160, Lichtwer Pharma GmbH, Berlin) were studied in 12 healthy male subjects. After a single oral dose of 300, 900, or 1800 mg of dried hypericum extract (250, 750, or 1500 micrograms hypericin and 526, 1578, or 3156 micrograms pseudohypericin), plasma levels were measured with a modified highly sensitive high-pressure liquid chromatography (HPLC) method (lower detection limit 0.1 ng/mL) up to 3 days. The median maximal plasma levels were 1.5, 4.1, and 14.2 ng/mL for hypericin and 2.7, 11.7, and 30.6 ng/mL for pseudohypericin, respectively, for the three doses given above (interim evaluation of four volunteers). The median elimination half-life times of hypericin were 24.8 to 26.5 hours, and varied for pseudohypericin from 16.3 to 36.0 hours. Ranging between 2.0 to 2.6 hours, the median lag-time of absorption was remarkably prolonged for hypericin when compared to pseudohypericin (0.3 to 1.1 hours). The areas under the curves (AUC) showed a nonlinear increase with raising dose; this effect was statistically significant for hypericin. During long-term dosing (3 x 300 mg/day), a steady-state was reached after 4 days. Mean maximal plasma level during the steady-state treatment was 8.5 ng/mL for hypericin and 5.8 ng/mL for pseudohypericin, while mean trough levels were 5.3 ng/mL for hypericin and 3.7 ng/mL for pseudohypericin. In spite of their structural similarities there are substantial pharmacokinetic differences between hypericin and pseudohypericin.

Kinetics of hexobarbital and dipyrone in critical care patients receiving high-dose pentobarbital.

The effect of pentobarbital treatment in a mean dose of 30 mg/kg/day on the clearance of hexobarbital (Evipan) and dipyrone (Novalgin) has been evaluated in critical care patients receiving a large number of drugs as comedication. Eleven patients treated with pentobarbital showed a hexobarbital half-life of 2.79 h and a total plasma clearance of 9.80 ml X min-1 X kg-1 as compared to 10 patients without pentobarbital administration in whom there was a significantly longer half life (6.92 h) and lower clearance (2.97 ml X min-1 X kg-1). The kinetics of hexobarbital were correlated with the urinary excretion of D-glucaric acid, a non-invasive parameter of drug metabolising activity. In 10 patients on pentobarbital, the total plasma clearance of N-4-methyl-aminoantipyrine, the active form of dipyrone, did not differ from that in 8 patients not receiving pentobarbital. As drug kinetics show great variability in these patients, it is difficult to discriminate enzyme induction from other mechanisms, for example competitive inhibition or changes in volume of distribution. In the presence of pentobarbital, however, induction of drug metabolising enzymes should be considered as a possible reason for the higher clearance of hexobarbital.

D-glucaric acid excretion in critical care patients--comparison with 6 beta-hydroxycortisol excretion and serum gamma-glutamyltranspeptidase activity and relation to multiple drug therapy.

The incidence of increased drug metabolism activity as a consequence of multiple drug therapy at a surgical intensive care ward has been studied non-invasively by determinations of daily urinary D-glucaric acid (GA) excretion rates. Among 165 randomly selected patients, GA excretion was stimulated in 76 cases (= 46%). Exploratory data analysis showed that increases in GA excretion are primarily due to administration of barbiturates (pentobarbitone, Nembutal), miconazole (Daktar) and, to a lesser extent, neuroleptics. Surprisingly, the large number of simultaneously administered additional drugs failed to increase GA excretion. Urinary 6 beta-hydroxycortisol (6 beta-OHF) and 17-hydroxycorticosteroid (17-OHCS) excretion rates were correlated in 34 patients with GA excretion; patients not receiving known enzyme inducers showed low GA values but high 6 beta-OHF and 17-OHCS values, however, with a ratio of 6 beta-OHF/17-OHCS in the normal range. Patients receiving high dose pentobarbitone treatment failed to exhibit significantly increased 6 beta-OHF and 17-OHCS or 6 beta-OHF/17-OHCS values. Miconazole treatment resulted in a significantly increased ratio of 6 beta-OHF/17-OHCS. gamma-Glutamyltranspeptidase activity in serum showed no correlation with GA excretion (n = 91).