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The Influence of St. John's Wort on CYP2C19 Activity with Respect to Genotype

From the Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Dr. L.-S. Wang, Dr. Zhu, Dr. El-Aty, Dr. G. Zhou, Dr. Z. Li, Dr. Chen, Dr. Liu, Dr. Tang, Dr. An, Dr. Q. Li, Mr. D. Wang, Dr. H.-H. Zhou) and Department of Cardiovasology, First Affiliated Hospital, Guangzhou Medical College, Guangzhou, China (Dr. Wu).

Address for reprints: Professor Hong-Hao Zhou, Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan 410078, China.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Induction of cytochrome P450 isozymes is the major cause for clinical drug interactions of St. John's wort. The relationships of St. John's wort to cytochrome P450 isoforms have been fully investigated, but its effect on CYP2C19 is lacking. Thus, the aim of the present study was to observe the effect of St. John's wort on CYP2C19 activity using CYP1A2 as a control. Twelve healthy adult men—6 extensive metabolizers of CYP2C19 (2C19^*1/2C19^*1) and 6 poor metabolizers (4 2C19^*2/2C19^*2 and 2 2C19^*2/2C19^*3)—were enrolled in a two-phase, randomized, crossover manner. All subjects took a 300-mg St. John's wort tablet or placebo three times daily for 14 days, and then the activities of CYP2C19 and CYP1A2 were measured using mephenytoin and caffeine. It was found that St. John's wort treatment significantly increased CYP2C19 activity in CYP2C19 wild-genotype subjects, with urinary 4'-hydroxymephenytoin excretion raised by 151.5% ± 91.9% (p = 0.0156), whereas no significant alteration was observed for CYP2C19 poor metabolizers. Repeated St. John's wort administration did not affect the CYP1A2 phenotypic ratio for both CYP2C19 genotype subjects. In conclusion, St. John's wort is an inducer to the human CYP2C19, and clinicians should pay great attention when St. John's wort is added to or withdrawn from an existing drug regimen containing substrates for such enzymes.

Key Words: St. John's wort • rifampicin • CYP2C19 • drug interactions • poor metabolizers • extensive metabolizers

As a natural product, it has been viewed as a safe treatment for a long time; however, recent reports indicate that St. John's wort interacts with a number of different medicines, which could result in potentially serious adverse reactions. Since 1998, seven spontaneous cases of a reduced anticoagulant effect of warfarin (i.e., a decreased international normalized ratio [INR]) associated with the concomitant use of St. John's wort tablets have been published. The decrease in INR was thought to be clinically significant.³ During St. John's wort treatment, another 4 patients who received transplantation suffered graft rejection with decreased blood concentrations of cyclosporine.^4-7 Unplanned pregnancies occurred in 9 women taking oral contraceptives and St. John's wort tablets as well.⁷ In addition, theophylline, HIV protease inhibitors, and some other kinds of drugs are also likely to interact with St. John's wort.^8,9

Serious cases of clinical drug interactions of St. John's wort sparked rigorous scientific investigations. Progresses in this direction identified that St. John's wort is a potent agonist of the orphan nuclear receptor pregnane X receptor.^2,10 In addition, repeated St. John's wort treatment increases the expressions of cytochrome P450 (CYP) 3A4 and P-glycoprotein,¹¹ thereby promoting the in vivo elimination of a number of clinically used medications. Excluding CYP3A4, the other P450 isoforms, such as 1A2, 2C9, 2D6, are also subjected to be involved in the clinical interactions of St. John's wort treatment. Wang and his coworkers¹² found that long-term administration of St. John's wort resulted in a significant and selective induction of CYP3A activity in vivo, but the activities of 2C9, 1A2, or 2D6 did not alter. To date, the in vivo effect of St. John's wort on CYP2C19 remains unclear, although the extract of St. John's wort contains potent inhibitors of CYP2C19 in vitro.

CYP2C19 is a clinically important isoform that is responsible for the biotransformation of diazepam, omeprazole, certain barbiturates, chloroguanide (INN proguanil), and many other clinically used drugs.¹³ CYP2C19 is almost exclusively responsible for S-mephenytoin 4-hydroxylation, and S-mephenytoin has been established to be an ideal probe to measure the activity of such enzymes in vivo^14,15 by measuring urine 4-hydroxymephenytoin.¹⁶ Genetic polymorphisms of CYP2C19 have resulted in poor or extensive metabolizers. Two defective alleles, CYP2C19^*2 (m1: 681 G A) and CYP2C19^*3 (m2: 636 G A), have been characterized as the main genetic factor for CYP2C19 poor metabolizers.¹⁷ This study was designed to observe the effect of long-term use of St. John's wort on CYP2C19 activity, using the activity of CYP1A2 as a control.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Subjects
Eighteen unrelated healthy adult men, weighing 60.4 ± 6.7 kg (mean ± SD), were recruited for this study. Twelve of them were recruited from a total of 101 healthy Chinese volunteers who had been screened for the CYP2C19 genotype as previously described.^13,18 Six individuals were homozygous for the wild-type allele (CYP 2C19^*1/^*1), 4 were homozygous of the allele with a 681 G A m1 mutation (CYP 2C19^*2/^*2), and the other 2 were heterozygous of allele m1 and the allele with the 636 G A m2 mutation (CYP 2C19^*2/^*3). After our study was approved by the Ethics Committee Board of Central South University, Hunan, China, all subjects gave written informed consent to participate in our study. They all finished the entire protocol of this study. All participants were required to be from ages 18 to 25 years (mean = 21.9 ± 0.9 years), to be non-smokers, and to have a standard body mass index between 18 and 30 kg/m². The participants also must have been in good health, with no clinically relevant condition identified from physical examination, electrocardiogram, and medical records. Participants receiving over-the-counter medications, St. John's wort, or other herbal medicines within the past month; ingesting alcohol within 2 weeks before admission; receiving an investigational remedy within 2 months of enrollment; or having a previous history of alcohol or drug abuse and an allergy to St. John's wort, caffeine, and mephenytoin were excluded from completion of the experiments.

Study Design
This study was carried out using a two-phase crossover design with a 5-week interval between phases. In each phase, 12 volunteers (6 2C19^*1/2C19^*1, 4 2C19^*2/2C19^*2, and 2 2C19^*2/2C19^*3) received placebo or an oral St. John's wort tablet containing 0.3% hypericin and a minimum 4% hyperforin (St. John's wort extract, research grade, 300 mg per tablet, Hypericum Buyers Club, CA) three times daily for 14 days. On the 15th day, after voiding their bladders, all subjects were given a single oral dose of 100 mg mephenytoin and 300 mg caffeine at the same time. Aliquot samples of urine were taken at 0 to 8 hours postadministration and stored at -20°C until analyzed. Venous blood samples (5 mL) were collected into heparinized tubes from the antecubital vein 6 hours after administration. Blood samples were centrifuged at 3500g for 10 min, and the plasma was harvested and stored at -20°C pending assay. No medications, including alcohol, were permitted for at least 3 weeks before and during the study. All subjects were monitored for the development of adverse effects commonly associated with St. John's wort, caffeine, and mephenytoin (such as dry mouth and gastrointestinal upset).

Analytical Procedure
Serum concentrations of caffeine (1,3,7-trimethylxanthine, 137X) and paraxanthine (1,7-dimethylxanthine, 17X) were quantified by Hewlett-Packard 1050 series high-performance liquid chromatography (HPLC) with ultraviolet detection at a wavelength of 282 nm according to the method described previously with minor modifications.¹⁹ Briefly, a mixture of a 200-µL aliquot of plasma and 100 µL of ß-hydroxyethyltheophylline (Sigma Chemical Co., St. Louis, MO) as an internal standard were treated with 400 mg ammonium sulfate and extracted with 5 mL chloroform and isopropanol (9:1 [vol/vol]). The residue was reconstituted with 100 µL mobile phase, which consisted of 90% 0.01 mol/L NaH₂PO₄ and 10% acetonitrile. A portion of 20 µL was injected onto a Zorbax eclipse XDB-C8 column (particle size, 5 µm; 4.6 x 150 mm; Agilent, Palo Alto, CA). The validated limit of quantification (LOQ) was 0.6 µmol/L and 0.5 µmol/L for 137X and 17X, respectively. The within-day (interday) coefficients of variation for 137X were 13.2%, 6.6%, and 11.7% at 0.7, 2, and 10 µmol/L, respectively, and the day-to-day (intraday) coefficients of variation at the corresponding concentrations were 11.2%, 9.5%, and 12.5%. For 17X, at 0.8, 2, and 5 µmol/L, the within-day coefficients of variation were 9.8%, 7.2%, and 12.3%, and the day-to-day coefficients of variation were 10.7%, 8.4%, and 11.7%, respectively.

The assay for 4-hydroxymephenytoin excreted in the urine was modified as described previously.²⁰ Briefly, the HPLC system was also composed of a Hewlett-Packard 1050 series with ultraviolet detection. Urine 4'-hydroymephenytoin and internal standard phenobarbital were extracted with absolute diethyl ether after enzymatic deconjugation. The residue remaining after evaporation was dissolved in 50 µL of eluate, and 20-µL preparations were measured by HPLC with a Zorbax eclipse XDB-C8 column (4.6 mm, ID x 15 cm, Agilent). The mobile phase was a mixture of 24% acetonitrile and 76% water. The flow rate was 1 mL/min, and the column elutes were monitored at 204 nm. The intra- and interday variations were less than 12% and 14%, respectively.

Statistical Analysis
Data are expressed as mean ± SE or mean and 95% confidence intervals (CIs). The treatment effect was analyzed by the rank sum test. Differences were regarded as statistically significant when p < 0.05.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Two subjects felt a little dizzy when they used the St. John's wort in the study. Overall, the treatments in the clinical trial were well tolerated, and the 18 volunteers completed the whole fixed-order protocol. No serious adverse events were recorded.

In this study, we used urinary 4'-hydroxymephenytoin as an index for CYP2C19 activity. As shown in Figure 1 and Table I, the recovery of 4'-hydroxymephenytoin in urine increased from 64.0% to 285.3% by 151.5% ± 91.9% (p = 0.0156) in CYP2C19 wild-genotype subjects after a 14-day administration of 900 mg St. John's wort. On the other hand, the recovery of 4'-hydroxymephenytoin in CYP 2C19^*2/^*2 and ^*3 individuals exhibited two-way alterations following St. John's wort treatment. As a whole, there is no significant difference between placebo and/or St. John's wort treatment phases. The distributions of 17X/137X, a phenotypic ratio of CYP1A2, are displayed in Figure 2 and Table I. Following 14-day treatments with placebo and/or St. John's wort, two-way alteration was observed in the two subject groups.

View larger version (12K): [in this window] [in a new window]   Figure 1. The 0- to 8-hour urine recovery of 4-hydroxymephenytoin in 12 subjects after a 14-day treatment of placebo or St. John's wort tablet.

View larger version (12K): [in this window] [in a new window]   Figure 2. Caffeine metabolic ratio 17X/137X in 12 subjects after a 14-day treatment of placebo or St. John's wort.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
CYP2C19 activity was well described to have a genetic bimodal distribution in the population. In the placebo phase of this study, we found that the 2C19 activity somewhat overlapped between the extensive metabolizers and the poor metabolizers, but in the St. John's wort phase, the activity in the wild 2C19 genotype was significantly higher than in poor metabolizers.

It has been demonstrated that there is a single constitutive androstane receptor (CAR) binding site in the CYP2C19 promoter; this androstane-responsive element (CAR-RE) can bind both CAR and the pregnane X receptor (PXR).²¹ This study suggests that CYP2C19 may be induced by the corresponding receptor agonists. Our earlier study had shown that rifampin, a PXR agonist, is an inducer of 2C19, and its inducing effect is genotype dependent.^22,23 Johne and his coworkers²⁴ have even supposed that CYP2C19 might be involved in the interactions between the PXR agonist in St. John's wort and amitriptyline. However, the relationship between St. John's wort and 2C19 remains unclear. At the same time, St. John's wort was reported to contain potent inhibiting constituents for the activity of P450 enzymes in vitro, including CYP2C19.²⁵ Thus, it seems that St. John's wort has the potential to cause temporally distinguishable inhibition and an inducing effect on the CYP2C19 isoform. In this study, we found that the activity of 2C19 markedly increased in ^*1/^*1 subjects, in contrast to ^*2/^*2 and ^*2/^*3 individuals, after intake of St. John's wort tablets for 14 days. Our study demonstrated that St. John's wort is a potent inducer of CYP2C19. To our knowledge, this is the first report about the inductive potential of St. John's wort on CYP2C19 in vivo.

In clinical situations, the addition or withdrawal of St. John's wort from an existing drug regimen containing CYP2C19 substrates, such as omeprazole, diazepam, and proguanil, may cause pronounced concentration alterations and should be done gradually and with appropriate monitoring of therapeutic efficacy and adverse events since well-documented interactions have been recorded between St. John's wort and the CYP3A4 substrates cyclosporine and oral contraceptives.⁷

Clinical observations suggest a potential metabolic interaction between St. John's wort and theophylline, a 1A2 probe drug.⁹ Karyekar and his coworkers,²⁶ in their in vitro study, found that the expression of CYP1A2 in the LS180 intestinal cells was greatly increased by St. John's wort in a concentration-dependent manner. This indicates that CYP1A2 is another potential cytochrome P450 target enzyme of St. John's wort. However, at the entire body level, the short-term coadministration of St. John's wort did not alter the plasma theophylline concentrations and the 1A2-mediated metabolic ratio.^12,27 Prolonged St. John's wort exposure, however, may augment the minor contribution of CYP3A4 and CYP2E1 pathways involved in theophylline biotransformation, which could account for one previous reported drug interaction case by Gurley et al.²⁸ In line with these observations, we did not find any significant differences in the activity of 1A2 after 2 weeks of St. John's wort administration.

As currently known, rifampin and St. John's wort belong to the same type of inducer. They both interact with other drugs in clinical situations by activating PXR.^10,29 Similar to St. John's wort, rifampin has also been well documented clinically to interact with the same pattern of drugs, such as warfarin, oral contraceptives, cyclosporine, theophylline, and so on.³⁰ However, these two agents seems to have various effects on CYP1A2 activity. Although rifampin has proven to be a potent inducer to this enzyme,³¹ our study and others have found that St. John's wort does not affect 1A2 activity.^12,27 Since the pregnane X receptor activated by St. John's wort does not enhance the activity of CYP1A2, PXR must not be involved in the regulation of such an enzyme. Therefore, the inducing effect of rifampin on CYP1A2 must be through a mechanism other than PXR.

In summary, our study demonstrated that the ingestion of St. John's wort does not change the activity of CYP1A2 but substantially increases the activity of CYP2C19. Clinicians should pay great attention when St. John's wort is added to or withdrawn from an existing drug regimen containing a substrate of CYP2C19.

	FOOTNOTES

 
This work was supported by the National Natural Science Foundation of China grants F30130210, C30000211, and C30200346 and the China Medical Board of New York grants 99-697 and 01-755.

DOI: 10.1177/0091270004265642

Submitted for publication April 17, 2003; Revised version accepted March 21, 2004.

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