Drug-Herb Interaction: Effect of St John’s Wort on Bioavailability and Metabolism of Procainamide in Mice

By Dasgupta, Amitava Hovanetz, Melissa; Olsen, Margaret; Wells, Alice; Actor, Jeffrey K

* Context.-St John’s wort induces the activity of the cytochrome P450 enzyme system causing treatment failure because of increased metabolism of many drugs. Procainamide is metabolized by a different pathway to N-acetyl procainamide. Objective.-To study St John’s wort- procainamide interaction using a mouse (Swiss Webster) model.

Design.-One group of mice (group A, 4 mice in each group) was fed St John’s wort each day for 2 weeks (last dose 1 day before administration of procainamide); another group (group B) received the same dose of St John’s wort for 1 week. The third group (group C) received only a single dose 1 hour before administration of procainamide, and the control group (group D) received no St John’s wort. All groups later received a single oral dose of procainamide. Blood was drawn 1, 4, and 24 hours after administration of procainamide and concentrations in serum of procainamide as well as N-acetyl procainamide were measured using immunoassays.

Results.-The procainamide concentrations 1 hour after administration was highest in group C (mean, 11.59 [mu]g/mL) followed by group A (9.92 [mu]g/mL), whereas group B (7.44 [mu]g/ mL) and control group D (7.36 [mu]g/mL) showed comparable values. The concentration in group C was significantly greater than the control group D (P = .03, 2-tailed independent t test). N-Acetyl procainamide concentrations and estimated half-life of procainamide among groups were comparable. In a separate experiment when mice were fed purified hypericin, the active component of St John’s wort, a signifi- cant increase in bioavailability (53%) of procainamide was observed compared with the control group.

Conclusions.-St John’s wort has an acute effect to increase bioavailability of procainamide but has no effect on its metabolism.

(Arch Pathol Lab Med. 2007;131:1094-1098)

(ProQuest-CSA LLC: … denotes formula omitted.)

St John’s wort is a popular antidepressant available without a prescription from health food stores throughout the United States. According to a study on the use of herbal remedies in the United States, the most commonly used was ginseng followed by Echinacea, Ginkgo biloba, and St John’s wort.1 Most commercially sold St John’s wort preparations in the United States are alcoholic or dried extract of hypericum, a perennial aromatic shrub. The main mechanisms of drug-herb interaction involve induction or inhibition of hepatic or intestinal metabolism of drugs by cytochrome P450 (CYP). CYP3A4 is the most abundant isoenzyme of CYP and is responsible for metabolism of more than 73 medications and numerous endogenous compounds.2 The active components of St John’s wort induce CYP3A4 and other isoenzymes.3-5 In particular, hyperforin is thought to be responsible for isoenzyme induction through activation of a nuclear steroid/pregnane and xenobiotic receptor.6 Another mechanism of drug-herb interaction involves induction or inhibition of intestinal drug efflux pumps including P-glycoprotein and multiple resistance proteins.7 St John’s wort also modulates P- glycoprotein drug transporter, and hypericin may be the active ingredient that is responsible for this effect.8,9 Therefore, it is likely that St John’s wort will interact with drugs that are metabolized via CYP3A4 or where P-glycoprotein pumps play a role in disposition of the drug.10

Self-medication with St John’s wort may cause treatment failures because of increase in clearance of many prescribed drugs. These include immunosuppressants (cyclosporine and tacrolimus), human immunodeficiency virus protease inhibitors, human immunodeficiency virus nonnucleoside reverse transcriptase inhibitors metabolized via CYP3A4, antineoplastic drugs such as irinotecan and imatinib mesylate, amitriptyline, digoxin, fexofenadine, benzodiazepines, theophylline, oral contraceptives, and warfarin.11-14 Unrecognized use of St John’s wort is frequent and may have an important influence on the effectiveness and safety of drug therapy during hospital stays.15

A case report describing an interaction between St John’s wort and theophylline has been reported.16 However, Morimoto et al17 recently observed no significant change in pharmacokinetics of theophylline in plasma after 15 days’ treatment with St John’s wort in 12 volunteers. Reduced plasma levels of methadone were also observed in the presence of St John’s wort resulting in reappearance of withdrawal symptoms.18 Sugimoto et al19 reported that St John’s wort significantly reduces plasma concentrations of the cholesterol- lowering drug simvastatin, which is metabolized by CYP3A4 in the intestinal wall and liver. On the other hand, St John’s wort did not influence plasma pravastatin concentration. However, St John’s wort has no effect on the pharmacokinetics of carbamazepine in healthy volunteers.20

Interaction between St John’s wort and digoxin is of clinical significance. Johne et al21 reported that 10 days’ use of St John’s wort could result in a decrease of trough serum digoxin concentrations by 33% and peak digoxin concentrations by 26%. Digoxin is a substrate for P-glycoprotein, which is induced by St John’s wort. Durr et al22 also con- firmed lower digoxin concentrations in healthy volunteers who concurrently took St John’s wort. St John’s wort dose and preparation also affect pharmacokinetics of digoxin.23 Tannergren et al24 reported that repeated administration of St John’s wort significantly decreases bioavailability of R- and S-verapamil. This effect was caused by induction of first-pass metabolism by CYP3A4 most likely in the gut.

Studies have demonstrated that CYP enzyme induction by St John’s wort depends on the hyperforin content, and products that do not contain substantial amounts of hyperforin ([mu]1%) may not show clinically significant interactions with drugs.10 Arold et al25 demonstrated that low hyperforin-containing St John’s wort had no significant interaction with alprazolam, caffeine, tolbutamide, and digoxin.

Procainamide is a type 1 antiarrhythmic agent widely used to treat a variety of atrial and ventricular arrhythmias. It is marketed as a hydrochloride salt. The drug is metabolized by acetylation mediated by N-acetyltransferase, and the resulting metabolite N-acetyl procainamide (NAPA) also has pharmacologic activity. Procainamide is usually used as a long-term therapy, and therapeutic drug monitoring is essential for proper patient management as well as to avoid drug toxicity. It is possible that a patient receiving procainamide may also take St John’s wort. We studied St John’s wort-procainamide interaction using a mouse model. Roberts et al26 demonstrated that, compared with humans, mouse strains are slow acetylators of procainamide, whereas rat strains are fast acetylators. Moreover, differences among different mice strains (including Swiss mice) of metabolism of procainamide were small. In contrast, among humans, mixed acetylator phenotype varied between 11% to 38%. Therefore, if St John’s wort has any effects on metabolism of procainamide, it will be more remarkable in slow acetylators and all mice in the same breed should behave similarly.

MATERIALS AND METHODS

Swiss Webster mice (female, 8-10 weeks of age) were purchased from Harlan (Indianapolis, Ind). Mice were allowed to rest for at least 1 week following receipt before experimentation. St John’s wort (liquid extract of Hypericum perforatum) was purchased from a local herbal store (Gaia Herbs, Brevard, NC). This brand of St John’s wort is most popular in the Houston area as determined by an informal survey of several local herbal stores. Procainamide hydrochloride and hypericin were purchased from Sigma-Aldrich Chemical Company (St Louis, Mo). Concentrations of procainamide and NAPA in sera of mice were determined by the respective fluorescence polarization immunoassay (FPIA) marketed by Abbott Laboratories (Abbott Park, Ill), and the assays were run using the AxSYM analyzer (Abbott). The experimental protocol involving mice was approved by the animal welfare committee of the University of Texas Health Sciences Center at Houston.

To confirm the presence of hypericin and hyperforin in the St John’s wort used in this study, we performed thin layer chromatography analysis using silica gel plates (Whatman Partisil silica gel 60 A[degrees] , layer thickness 250 mm, with fluorescent indicator [Fischer Scientific, Houston, Tex]). The developing solvent had a composition of n-heptane-acetone-t-butyl methyl ether- 96% acetic acid (33:35:30:2, vol/vol/vol/vol). Liquid extract of St John’s wort was directly spotted on the plate. The hypericin and hyperforin standards were also spotted on the plate for comparison. After developing plates, excess solvent was allowed to dry at room temperature, and then spots were visualized under UV light as described by Orth et al.27 After visualizing spots under UV light, plates were sprayed with a charring agent (0.5% =- napthol, 5% sulfuric acid in absolute ethanol) followed by heating to further observe the spots.

St John’s wort extract was diluted with water (1:3, vol/vol) to reduce ethyl alcohol content of the extract to 20%. Mice were separated into 4 different groups. Group A (4 mice) received a single dose of St John’s wort (75 [mu]L, diluted extract) for 2 weeks. The last dose of St John’s wort was given 24 hours before administration of procainamide. Group B (4 mice) received the same dose of St John’s wort for only 1 week. Group C (4 mice) received only a single dose of St John’s wort 1 hour before administration of procainamide (to investigate acute effect of St John’s wort), and group D (4 mice) received no St John’s wort. Then all groups of mice received a single dose of procainamide (100 mg/kg) following food withdrawal of 1 hour before administration of procainamide. Except for the group C mice (who received a single dose of St John’s wort 1 hour before receiving procainamide), there was a 24-hour time difference between the last dose of St John’s wort and the dose of procainamide. The dose of procainamide was chosen in light of the kinetics of metabolism of procainamide in rats.28 Mice were dosed with St John’s wort and later procainamide by gavage. Blood was withdrawn 1, 4, and 24 hours after administration of procainamide by retro-orbital bleeding. Concentrations of both procainamide and NAPA were determined using the respective FPIA assay on an AxSYM analyzer as described previously. The half-life of procainamide was calculated by using mean procainamide concentrations in each group at 1-hour (Ct1) and 4-hour (Ct2) intervals. We divided 0.693 by K to calculate the half-life and the value of K was determined from the standard formula: …

To ensure that components of St John’s wort did not interfere with the FPIA assay for procainamide and NAPA, we supplemented 1-mL drug-free serum with 100 [mu]L of St John’s wort and then measured both procainamide and NAPA concentrations. Mice were also fed with 200 [mu]L of St John’s wort in a single dose, and blood was withdrawn after 1 hour to determine procainamide and NAPA concentrations. We deliberately selected a much higher dose of St John’s wort to feed mice to investigate the worstcase scenario.

In a separate experiment, we investigated the effect of hypericin, an active component of St John’s wort, on bioavailability of procainamide. A standard solution of hypericin was prepared in absolute ethanol. Then 10 [mu]L of this standard solution was diluted with 90 [mu]L of water and fed to mice as a single dose (each dose contained 10 [mu]g of hypericin). We fed 3 mice with a single dose of hypericin 1 hour before administration of a single dose of procainamide. Three mice in the control group received only procainamide. Blood was withdrawn 1, 4, and 24 hours after administration of procainamide, and both procainamide and NAPA concentrations were determined as described previously.Half-life of procainamide in both groups was calculated as described previously.

To ensure that ethyl alcohol does not alter absorption of procainamide, 3 mice were fed with 75 [mu]L of vehicle control (20% ethanol in water) 1 hour before administration of a single dose of procainamide. Three mice were used as control. After a single oral dose of procainamide, blood was withdrawn after 1 hour. Procainamide and NAPA concentrations were measured by immunoassays.

Statistical analyses were performed using an independent t test, 2-tailed. Statistical significance was set at a confidence interval of 95% or higher (P [mu] .05).

RESULTS

The vehicle (ethyl alcohol) for procainamide did not have any effect on the bioavailability of procainamide in mice. Mice fed vehicle 1 hour before procainamide (100 mg/kg) administration did not exhibit any statistically significant difference from mice given procainamide alone. Drug and metabolite levels in the group receiving alcohol (procainamide, 8.53 +- 1.56 [mu]g/mL; NAPA, 0.94 +- 0.24 [mu]g/mL) were indistinguishable from those that had not received alcohol (procainamide, 8.98 +- 1.26 [mu]g/mL; NAPA, 1.07 +- 0.18 [mu]g/mL).

To assess the validity of the assay for procainamide and NAPA, mice were fed a single dose of 200 [mu]L of St John’s wort. This dose of St John’s wort (200 [mu]L) is 2.7 times higher than the dose (75 [mu]L) used for study of St John’s wort-procainamide interaction. Following blood sampling, no apparent procainamide or NAPA concentrations were observed. In addition, drug-free serum was supplemented with 100 [mu]L of St John’s wort and then used for procainamide and NAPA determinations. Again, no apparent procainamide or NAPA was measured. These results indicate that FPIA assay for procainamide and NAPA can be used to study St John’s wort- procainamide interactions in mice. The FPIA assays for both procainamide and NAPA on the AxSYM analyzer have excellent precisions with within- and between-run imprecisions less than 4%.

Preliminary experiments indicated that peak procainamide concentration can be observed within 1 hour after feeding procainamide in mice. Therefore, 3 time points (1, 4, and 24 hours) were used to withdraw blood from mice to study St John’s wort- procainamide interaction. The mean procainamide concentrations 1 hour after administration of procainamide were 9.92 [mu]g/mL in group A, 7.44 [mu]g/mL in group B, 11.59 [mu]g/mL in group C, and 7.36 [mu]g/mL in group D (Tables 1 and 2). The concentrations of procainamide in group C were significantly greater than the concentrations of procainamide in the control group of mice (group D) by an independent t test, 2-tailed (P = .03). Although the mean concentration of procainamide was higher in group A compared with the control group, the difference was not statistically significant. These results indicate that bioavailability of procainamide was significantly increased when mice were fed with St John’s wort 1 hour before administration of procainamide. However, this effect appears to be an acute effect because it was not present when mice were fed with St John’s wort for 1 week or 2 weeks even though there was a 24-hour gap between the last dose of St John’s wort and administration of procainamide.

The ratio between NAPA and procainamide concentrations was much lower in 1-hour serum specimens compared with 4-hour serum specimens. However, the ratio was comparable among all groups, despite the fact that the serum concentrations of procainamide were higher in group C compared with any other groups (Table 2).

The mean concentrations 4 hours after administration of procainamide were comparable among all groups, and NAPA levels were also comparable, indicating that St John’s wort has no significant effect on the metabolism of procainamide in mice. Procainamide was completely cleared from circulation in all mice 24 hours after administration of procainamide because no detectable level of either procainamide or NAPA was observed in sera of mice collected 24 hours after administration of procainamide (Table 1). The calculated half- life of procainamide (using serum concentrations at 1 and 4 hours) after a single dose was 1.61 hours in group A, 1.81 hours in group B, 1.56 hours in group C, and 1.89 hours in group D. These values are comparable indicating that St John’s wort does not induce metabolism of procainamide by the liver.

To investigate the effect of hypericin, an active component of St John’s wort, we fed 3 mice (group E) with 10 [mu]g of hypericin as a single dose and then after 1 hour administered a single dose of procainamide. Three mice in the control group (group F) received only procainamide. The procainamide concentration in group E 1 hour after administration of procainamide was significantly greater than the procainamide concentration in the control group (group F) by an independent t test (P = .046, 2- tailed), indicating that acute ingestion of hypericin increases bioavailability of procainamide in mice (Figure). However, the concentrations of procainamide in groups E and F did not differ significantly in specimens collected from mice 4 hours after administration of procainamide. N-Acetyl procainamide concentrations were also comparable, and again complete clearance of procainamide was observed in all mice 24 hours after receiving a single dose of procainamide. The calculated half-life of procainamide (using serum concentrations at 1 and 4 hours) in group E (1.68 hours) was also comparable to the calculated halflife of group F (1.89 hours) indicating that acute ingestion of hypericin had no significant effect on acetylation of procainamide in liver by N-acetyltransferase.

COMMENT

Use of complementary and alternative medicine by the general population is on the rise not only in the United States but also worldwide. Herbal supplements are marketed under the ”Dietary Supplement Act” of 1994 and are readily available without prescription at many herbal stores throughout the United States. According to a survey of 3789 people, 43.1% of respondents used 1 or more complementary or alternative medicine modalities. The use of such remedies is equally prevalent among the white, African American, Latino, Asian, and Native American populations. 29 In the United States, the sale of herbal products increased from $200 million in 1988 to more than $3.3 billion in 1997.30 Projected sales are much higher in recent years. Although the general population considers herbal remedies as safe, toxicity and even death from the use of herbal remedies has been well documented in the literature. Unfortunately, toxic herbal products are also readily available in heath food stores despite warnings. Mills et al31 reported that in Canada 57% herbal stores still sold kava-kava 2 months after Health Canada issued a warning against toxicity of this herbal product.

Although clinical trials indicate that St John’s wort is as effective as Western medicines such as fluoxetine, sertraline, and imipramin32-34 in the treatment of depression, this herbal supplement should be used with extreme caution because of many reported interactions of St John’s wort with drugs. St John’s wort induces the CYP enzyme system and also modulates the P-glycoprotein system. St John’s wort extract or hypericin alone increases the P- glycoprotein expression in vitro in intestinal cells (LS-180V).35 Moreover, chronic treatment with St John’s wort extract increases the expression of P-glycoprotein in peripheral blood mononuclear cells of healthy volunteers by 4-fold in comparison with untreated cells.8 On the other hand, St John’s wort extract was also shown to inhibit intestinal Pglycoprotein. Transport of fexofenadine, a substrate of Pglycoprotein, was reduced after single-dose administration of St John’s wort. In contrast, long-term treatment did not cause a significant change in the disposition of fexofenadine. 36 Our results clearly indicate that St John’s wort does not induce N-acetyltransferase even after feeding mice with St John’s wort for 2 weeks. We chose to treat 1 group of mice with St John’s wort for 2 weeks because most studies indicated 2 weeks of use of St John’s wort is required for full activation of the enzyme systems.16,19,24 We assumed that if components of St John’s wort are capable of stimulating N-acetyltransferase, a 2-week period should be a valid experimental design. We also fed another group of mice with St John’s wort for 1 week to study any potential short-term effect of enzyme induction. We selected another group of mice to receive a single dose of St John’s wort 1 hour before further administration of procainamide to investigate any acute effects of procainamide on absorption and metabolism of procainamide.

Although St John’s wort was not able to alter metabolism of procainamide, a single dose of St John’s wort before exposure to procainamide significantly increased bioavailability of procainamide. This finding indicates that a component of St John’s wort may inhibit P-glycoprotein in gut for a short time thus increasing the bioavailability of procainamide. When we fed mice with a single dose of hypericin, 1 hour before exposure to procainamide, we observed 53% increase in bioavailability confirming our hypothesis that hypericin may be responsible for increased uptake of procainamide in mice. Wang et al36 reported that a single dose of St John’s wort inhibited intestinal P-glycoprotein as reflected in the pharmacokinetics of fexofenadine. Patel et al37 reported that hypericin inhibited P-glycoprotein mediated efflux of ritonavir by increasing its cellular uptake.

We conclude that acute ingestion of St John’s wort increases the bioavailability of procainamide in mice. However, St John’s wort has no effect on the metabolism of procainamide. Therefore, it is unlikely that components of St John’s wort induce N- acetyltransferase.

We are grateful to Semyon A. Risin, MD, PhD, for his assistance in oral feeding of reagents to mice.

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Amitava Dasgupta, PhD; Melissa Hovanetz, MD; Margaret Olsen, BS; Alice Wells, MT(ASCP); Jeffrey K. Actor, PhD

Accepted for publication February 1, 2007.

From the Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Amitava Dasgupta, PhD, Department of Pathology and Laboratory Medicine, University of Texas-Houston Medical School, 6431 Fannin, MSB 2.292, Houston, TX 77030 (e-mail: Amitava.Dasgupta@ uth.tmc.edu).

Copyright College of American Pathologists Jul 2007

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