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Laboratory of Drug Disposition and Pharmacogenetics, Departments of Pharmaceutical Sciences (J.S.M.), Psychiatry and Behavioral Sciences (J.L.D., C.L.D., J.S.W., B.B.G., H.A.G.), and Surgery (K.D.C.), Medical University of South Carolina, Charleston, South Carolina
(Received June 23, 2004; Accepted August 23, 2004)
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Abstract |
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0.05; time to reach maximum concentration in plasma, 3.0 ± 3.2 versus 3.1 ± 2.1 h; area under the plasma concentration versus time curve, 471 ± 183 versus 539 ± 240 h · ng · ml-1; half-life of elimination, 13.5 ± 4.3 versus 12.2 ± 5.6 h). Our results indicate that although a modest increase was observed in the alprazolam Cmax, typical doses of valerian are unlikely to produce clinically significant effects on the disposition of medications dependent on the CYP2D6 or CYP3A4 pathways of metabolism.
). Although they are currently promoted as a sedative/hypnotic, clinical trials are presently inconclusive with regard to the efficacy for insomnia (Houghton, 1999; Stevinson and Ernst, 2000; Krystal and Ressler, 2001).
Valerian supplements contain a complex mixture of chemical constituents (Shohet et al., 2001). The main constituents are valerenic acid and its derivatives contained in the volatile oil (Houghton, 1999). These main constituents are widely thought to contribute to the putative sedative effects, although clinical effects may be a result of synergistic activity from numerous constituents. The valepotriates have also been investigated for pharmacologic activity but are relatively unstable and are often not present in most commercial supplements (Bos et al., 2002). Minor constituents include various alkaloids, furanofuran lignans, and free amino acids (Houghton, 1999). Valerian is well recognized by its unpleasant odor that is attributed to isovaleric acid formation during processing and storage.
The widespread use of valerian supplements suggests that use with conventional medications is inevitable, and the potential for drug interactions is undefined (Fugh-Berman and Ernst, 2001; Markowitz et al., 2003b; Huang et al., 2004). The present study was undertaken in healthy volunteers to determine whether a valerian supplement containing known quantities of valerenic acid and its derivatives could alter the activity of two major drug-metabolizing enzymes, cytochrome P450 2D6 (CYP2D6) and CYP3A4 in healthy volunteers. These two enzymes were chosen since, together, they contribute to the metabolism of a substantial number of both prescription and nonprescription medications (Wrighton and Thummel, 2000; Zanger and Eichelbaum, 2000; Burk and Wojnowski, 2004). To our knowledge, this is the first clinical study assessing whether a standardized valerian supplement may participate in drug interactions mediated by any of the P450 enzymes.
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Materials and Methods |
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). All subjects enrolled in the study were nonsmokers and were determined to be healthy by medical history, physical examination, basic laboratory monitoring indices, and 12-lead electrocardiogram. Subjects abstained from caffeine-containing beverages and ethanol use during the study period. Valerian Product. The valerian supplement used in this study was donated by Dr. Willmar Schwabe GmbH and Co. (Karlsruhe, Germany). This product had been prepared by extraction of valerian roots with 70% ethanol. Each tablet contained 500 mg of the dry valerian root extract derived from a single lot source. The content of valerenic acids was determined as described below before study initiation.
Study Design and Drug Administration. This was an open-label, fixed treatment order, crossover study, with each subject serving as his or her own control. The clinical protocol has been extensively used in our laboratory to assess the effects of dietary supplements on P450 activity (Donovan et al., 2003, 2004; Markowitz et al., 2003a,b). Subjects were admitted to the Medical University of South Carolina's General Clinical Research Center (GCRC) overnight and began the baseline P450 activity assessment the following morning. After an overnight fast and urinary void, each subject was administered a 30-mg oral dose of DM (Robitussin Maxium Strength cough syrup; Whitehall-Robins Healthcare, Madison, NJ) and 2 mg of alprazolam (ALPZ) (Mylan Pharmaceuticals, Inc., Morgantown, WV) with 30 to 60 ml of water. To eliminate any influence of food on the absorption of probe drugs, subjects did not eat breakfast but were fed a standard lunch 4 h after drug administration. An 8-h urine collection for the purpose of determining DM to dextrorphan metabolic ratios (DMRs) began immediately after probe drug administration, as well as collection of multiple blood samples for ALPZ analysis. Blood samples (10 ml) were obtained immediately before (0 h) and after the administration of ALPZ at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 60 h. Subjects were discharged from the GCRC at the 12-h time point and returned for outpatient visits for each of the final four blood draws. Heparinized 10-ml Vacutainer (BD Biosciences, Franklin Lakes, NJ) blood collection tubes were used for sampling. Collected blood samples were stored on ice until plasma separation, after which plasma was immediately stored at -70°C until analysis.
After a minimum 7 day wash-out period, subjects were provided a 14-day supply of the valerian extract. The subjects were instructed to take two 500-mg tablets (1000 mg) nightly at bedtime between 9:00 PM and 12:00 AM. Valerian tablets were dispensed in preloaded medication organizers embossed with the days of the week (Mediset; Health Care Logistics Inc., Circleville, OH) in an effort to enhance subject compliance with dosing schedule and duration (Park et al., 1991).
After 14 days of nightly exposure to 1000 mg of valerian extract, the subjects were readmitted to the GCRC for a second overnight stay. The following morning, subjects were administered 30 mg of DM and 2 mg of ALPZ as occurred in the baseline phase with identical specimen collection times. The preadmission nightly valerian dosing regimen continued for an additional 48 h during sample collection. Four hours after probe drug administration, each subject was served the same standard lunch they consumed during the baseline phase.
Analytical Methods. DM, dextorphan, and ALPZ were determined using previously described high-performance liquid chromatography methods (Miller and DeVane, 1988; Hoskins et al., 1997). The pharmacokinetic software program WinNonlin (Pharsight, Mountain View, NC) was used to estimate ALPZ pharmacokinetics. Mean pharmacokinetic parameters, and the dextromethorphan to DMR at baseline and after valerian administration were analyzed using the paired t test. The level of significance was set at p = 0.05.
Laboratory analysis of the valerian supplement was undertaken before study initiation (ChromaDex Research and Development, Clearwater, FL). Analysis of tablets for valerenic acid, hydroxyvalerenic acid, and acetoxyvalerenic acid was performed using 10 tablets from the same lot used in the clinical study. The tablets were ground to a fine powder, and 1.6 g was dissolved in 60:40 acetonitrile/water. Samples were analyzed in duplicate using a Dionex Summit HPLC System (Dionex Corporation, Sunnyvale, CA). A linear gradient of 40 to 80% acetonitrile in an aqueous solution of 0.1% H3PO4 was performed over 20 min with a flow rate of 1.5 ml/min. The analytical column was a Luna C18 (2) 150 x 4.6 mm, 5-µm reversed phase column maintained at 25°C (Phenomenex, Torrance, CA). Detection was performed by UV absorption at 218 nm.
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Results |
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Valerian Tablet Analysis. A high performance liquid chromatogram of the valerian tablet used in this study is shown in Fig. 1. The valerian supplement utilized contained a total valerenic acid content of 5.51 mg/tablet. This included acetoxyvalerenic acid at 2.61 ± 0.26 mg/tablet, hydroxyvalerenic acid at 0.231 ± 0.005 mg/tablet, and valerenic acid at 2.67 ± 0.05 mg/tablet.
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CYP2D6 Activity: Dextromethorphan Metabolic Ratio. All 12 subjects metabolized DM extensively to its metabolite at baseline and after valerian administration. The DMR was 0.214 ± 0.025 at baseline and 0.254 ± 0.026 after valerian supplementation (p > 0.05). The DMR values for these subjects are presented in Fig. 2. There were no significant differences in the DMR values between baseline and after treatment with valerian.
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CYP3A4 Activity: Alprazolam Pharmacokinetics. The observed mean concentration versus time curves from 0 to 60 h for the 12 volunteers at baseline and after valerian treatment are shown in Fig. 3. Associated pharmacokinetic parameters obtained are presented in Table 1. The Cmax of ALPZ was increased by approximately 20% after treatment with valerian (p < 0.05). Although the AUC was increased after treatment with valerian, the AUCs were not significantly different. Other values were not significantly different between baseline and post-treatment phases (p > 0.05).
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Discussion |
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; Zou et al., 2002) or other P450 isoforms (Zou et al., 2002). However, it is often difficult to extrapolate in vitro studies to the in vivo situation when assessing complex mixtures of phytochemicals with unknown disposition (Kroon et al., 2004). Additionally, previous in vitro studies have not assessed the potential for P450 induction.
The present study focused on the activity of two major P450 isoforms, CYP3A4 and CYP2D6. Together, these isoforms are involved in the metabolism of an estimated 70% of prescription and nonprescription medications (Wrighton and Thummel, 2000; Zanger and Eichelbaum, 2000). The results indicate that supplementation with a valerian extract providing 10.2 mg of valerenic acids per day did not result in significant differences in CYP2D6 activity as indicated by the DMR. The magnitude of the observed changes in the present study reflects normal variability in DM metabolism rather than CYP2D6 inhibition (Zhang et al., 1992; Liston et al., 2002). The results also indicate that CYP3A4 activity was not significantly affected because no significant differences were observed in the AUC, oral clearance, or elimination half-life of ALPZ. A significant increase was observed in the Cmax of ALPZ (p < 0.05). However, the magnitude of the increase, approximately 20%, is unlikely to be of clinical significance. Thus, these results indicate that valerian is unlikely to have clinically relevant effects on the disposition of medications primarily dependent on the CYP2D6 or CYP3A4 pathways for metabolism.
The reason for the modest increase in the Cmax of ALPZ observed in this study is not clear. P-glycoprotein is not believed to play a significant role in the disposition of triazolo-type benzodiazepines such as triazolam or ALPZ (Perloff et al., 1999). It should be noted that valerian was not administered concomitantly with ALPZ in this study, due to the unknown consequences of possible additive pharmacodynamic effects. The volunteers were instructed to take the valerian product nightly before bedtime, in a manner similar to the way the product is generally consumed. It is possible that certain valerian constituents were present in vivo at the time of ALPZ dosing the next morning but were not present during the terminal elimination phase of ALPZ. These components could have produced a small inhibitory effect on first-pass hepatic CYP3A4 activity. However, ALPZ is a low-extraction compound that has a very high bioavailability, indicating that significant first-pass intestinal or hepatic metabolism does not occur to a significant extent (Smith et al., 1984). A future study could determine whether concomitant administration of valerian has more substantial effects on the Cmax of ALPZ or other probe drug substrates to clarify its mechanism of action.
In conclusion, our findings indicate that valerian is not likely to participate in clinically significant interactions with drugs that are metabolized by CYP3A4 or CYP2D6. However, this study must be regarded only as the initial investigation into the drug interaction potential of this popular supplement. Continued vigilance in the use of valerian and other dietary supplements is advisable, especially when used in combination with conventional medications with narrow therapeutic indices.
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Footnotes |
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ABBREVIATIONS: P450, cytochrome P450; ALPZ, alprazolam; AUC, area under the time versus concentration curve; Cmax, maximum concentration in plasma; DM, dextromethorphan; DMR, dextromethorphan to dextorphan metabolic ratio; Tmax, time to reach maximum concentration in plasma; GCRC, General Clinical Research Center.
Address correspondence to: Dr. John S. Markowitz, Medical University of South Carolina, Institute of Psychiatry, RM 246 North, Laboratory of Drug Disposition and Pharmacogenetics, 67 President Street, Charleston, SC 29425. E-mail: markowij{at}musc.edu
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) and after supplementation with valerian extract for 14 days (
). For clarity, error bars reflecting the standard deviations are shown above the line at baseline and below the line after supplementation. The Cmax of alprazolam was significantly increased after supplementation with valerian. There were no significant differences in other pharmacokinetic parameters of alprazolam after supplementation with valerian (p < 0.05).