Advances in Clinical Pharmacokinetics Ginkgo Ext

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					     . 2005, Volume 2, No.6 (Serial No.7)                    Journal of US -China Medical Science, ISSN 1548-6648,USA

             Advances in Clinical Pharmacokinetics of Herbal Medicines∗

            Lei Zhang***1, Yuliang Wang1, Peng Zou2, Xinzhu Pan1 , Hanming Zhang1 , Wansheng Chen**3

Abstract: Herbs have been used for treating various ailments since medicine began. The belief that natural
products are much safer than synthetic drugs has led to dramatic growth of herbal medicine usage. Like synthetic
drugs, herbal preparations also have potential to cause adverse effects and drug interactions. Knowledge of herbal
pharmacokinetics is needed to e   xplain and predict various events related to the efficacy and toxicity of herbal
preparations. However, Pharmacokinetics and drug interactions of herbal preparation have not been yet
systematically studied. Especially, the clinical pharmacokinetic studies on herbal preparations are limited to some
widely used herbs such as St.John’ Wort and Gingko biloba. In this review, clinical pharmacokinetics studies that
have been conducted for herbal medicine products since 2001 are evaluated. Scientifically controlled clinical
studies on various herb-drug interactions are also discussed.
Key words: pharmacokinetics; herbal; clinical; volunteer


      Herbs and their preparations have been used for treatment of various ailments since medicine began. The
most ancient plants thought to be of medical significance were discovered in prehistoric graves and are 60,000
years old. All over the world, there are all kinds of remedies based on herbal medicines. One important system is
traditional Chinese medicine. Other traditional herbal remedies are found in Africa, South and Central America,
India, Indonesia and Pacific Islands. However, the evidence for their quality, efficacy and safety isn’ based on
scientific methods but derived from the traditional use of the herbal medicines .
      Rapid growth has been seen in the herbal medicine market in recent years, as increasing number of
consumers are persuaded by the efficacy and safety of plant extracts. Nowadays 80% of the world’ population
uses medicines, which are directly or indirectly derived from plants. Worldwide, herbal medicines share 25%
pharmaceutical markets. The markets for branded non-prescription herbal medicines had grown from US$ 1.5
billion in 1994 to US$ 4.0 billion in 2000 in U.S. alone with the same trend being followed in European countries
as well[2].
      In the U.S., herbal products are used as dietary supplements without the rigorous testing required for other
drugs. The approach of the Canadian Health Protection Brach with respect to herbal products is similar to FDA’   s
whereas several European countries have legislative regulation of herbal products. With the popularity of herbal
products, the FDA has published draft guidance for industry on quality of botanical drug products and is expected

  Supported by the National Natural Science Foundation of China (30371746)
    Corresponding to Wansheng Chen(1968.7-), male, PhD, associate professor of Department of Pharmacy, Changzheng Hospital,
Second Military Medical University; Main research field: pharmacognosy and plant drug discovery.
     Lei Zhang (1977.12-), male, instructor of Department of Pharmacognosy, School of Pharmacy, Second Military Medical
University; Main research field: natural herbal medicines.
  Department of Pharmacognosy, School of Pharmacy, Second Military Medical University, Shanghai, Postcode: 200433, China;
  Department of Pharmacy, Faculty of Science, National University of Singapore, Postcode: 119260, Singapore;
  Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, Postcode: 200003, China.

                             Advances in Clinical Pharmacokinetics of Herbal Medicines

to introduce regulations for access to the medicinal products market. Products supported by good evidence may
achieve the status of medicines in the USA [1].
      Pharmacokinetics of herbal medicines is necessary to promote efficacy and safety of herbal remedies and
avoid adverse effects. Pharmacokinetic study on herbal medicines is a challenge due to their complex composition,
unknown active constituents and low plasma concentrations of metabolites. Animal tests normally are cheap and
easy to perform, but the parameters derived from animal sometimes can’ apply to human. Thus, clinical
pharmacokinetic parameters of herbal medicines become an important evidence for rational herbal remedies. With
increasing knowledge of active compounds and availability of high sensitive and selective analytical methods,
data on clinical pharmacokinetics and clinical drug interactions of certain herbs have been published recently. This
review summarizes the data on clinical pharmacokinetics and clinical drug interactions of some commonly used
herbal medicines. Database searches of Pubmed and Scifinder Scholar were performed, covering publications
published from 2001 to current. The key words used were pharmacokinetics, herbal, clinical or volunteer. No
restriction to the language of publication was applied in the searches. Only studies involving extracts of single
herbs or mixtures of components were included. All clinical studies of drug-herb interactions, except case reports,
were included. This review is an update to several reviews on clinic al pharmacokinetics and clinical drug-herb


     Extracts used in herbal preparation are always complex mixtures of hundreds of compounds. Concentrations
of single compound in final products are less than mg per dose. The resulting plasma concentrations are in ug to
pg per liter range. Therefore, the analytic methods used in pharmacokinetic studies must be sufficiently sensitive
and selective. Recently, advanced techniques are widely used such as GC-MS/MS, HPLC-MS/MS and
HPLC-CoulArray for phenolic compounds [1].
     For determination of volatile compounds in human plasma, automated headspace solid-phase
microextraction-gas chromatography (HP-SPME-GC) technique was used. For example, thymol in human plasma
could be measured by using automated HP-SPME-GC method with a limit of quantitation (LOQ) of 8.1ng/ml [3].
Compared with TLC, HPLC-DAD and GC, automated HP-SPME-GC is a more sensitive and selective method for
quantification of volatile compounds in human plasma.
     It was also reported that spectroscopic method could be used to determine the interaction of effective
component of Chinese herbs with human serum albumin [4].
1. St John's Wort (Hypericum perforatum)
     St John’ Wort (SJW) is a widely used herbal medicine for the treatment of depression. In U.S., Hypericum
preparations have become very popular in recent years and are sold on the OTC market as dietary supplements [5].
Sales in the USA increased 20-fold between 1995 and 1997, from US$ 10 million to US$ 200million annually [6].
In Germany, SJW was one of the most common antidepressants with the market share of more than 20% [7].
     SJW extraction contains several groups of components that could contribute to its pharmacological effects.
These components include naphthodianthrones (hypericin and pseudohypericin), flavonoids (rutin, hyperoside,
isoquercitrin, quercitrin and quercetin), phloroglucinols (hyperforin and adhyperforin) and bioflavonoids
(biapigenin and amenthoflavon). SJW preparations are frequently standardized to defined hypericin
concentrations usually in the range of 0.1% to 0.3% [1].

                             Advances in Clinical Pharmacokinetics of Herbal Medicines

     During the past three years, most SJW clinical pharmacokinetic studies focused on mechanism of drug
interactions. Ability of SJW to induce cytochrome P450 (CYP) 3A4 has been well established [8, 9]. Studies show
that hyperforin is a potent ligand for the pregnane X receptor that regulates expression of CYP3A4
monooxygenase [10]. It is reported that urinary excretion of 6ß       -hydroxycortisol increased after 14-day SJW
extracts treatment but urinary excretion of D-glucaric acid and free cortisol was unaffected, which suggests that
SJW extracts induced CYP3A4 activity [11]. The conclusion is also supported by a recent study [12]. After 14 days
of administration of SJW, 12 healthy volunteers were given 30 mg of dextromethorphan and 2 mg of alprazolam
along with 1 SJW, and SJW dosing regimen was continued for 48 hours. A 2              -fold decrease in the AUC for
alprazolam plasma concentration vs time (p<0.001) and a 2     -fold increase in alprazolam clearance were observed.
Alprazolam elimination half-life was shortened from a mean (SD) of 12.4 (3.9) hours to 6.0 (2.4) hours. This
suggests that long-term administration of St John's wort may result in diminished clinical effectiveness or
increased dosage requirements for all CYP 3A4 substrates. Effects of SJW on the pharmacokinetics of simvastatin
and pravastatin were reported too [13]. Long-term treatment with SJW decreases plasma concentrations of
simvastatin and its active metabolite but not of pravastatin because simvastatin i extensively metabolized by
cytochrome P 4503A4 in the intestinal wall and liver, which is induced by SJW.
     The effects of SJW on different human CYP450 phenotypes were determined by administrating probe-drug
cocktails of substrates. In one trial of 12 healthy subjects [14], substrates for several cytochrome P450 isozymes,
tolbutamide (CYP2C9), caffeine (CYP1A2), dextromethorphan (CYP2D6), oral midazolam (intestinal wall and
hepatic CYP3A), and intravenous midazolam (hepatic CYP3A) were administered to determine CYP activities.
The results showed that long-term SJW administration resulted in a significant and selective induction of CYP3A
activity in the intestinal wall and did not alter the CYP2C9, CYP1A2, or CYP2D6 activities. In another study [15],
caffeine, chlorzoxazone, and debrisoquin (INN, debrisoquine) were used to measure the effects of SJW on
CYP3A4, CYP1A2, CYP2E1, and CYP2D6 activities. It was found that SJW significantly induced the activity of
CYP2E1 and CYP3A4. Among female subjects, SJW produc ed significantly greater increases in CYP3A4
phenotypic ratios. This finding is suggestive of a sexual dimorphism in CYP3A4 inducibility.
     SJW induction of cytochrome P450 (CYP) 2C19 was also investigated [16]. Twelve healthy adult men (6
CYP2C19*1/CYP2C19*1, 4 CYP2C19*2/ CYP2C19*2 and 2 CYP2C19*2/CYP2C19*3) were enrolled in a
2-phase randomized crossover design. In each phase the volunteers received placebo or a 300 mg SJW tablet 3
times daily for 14 days. Then all subjects took a 20-mg omeprazole capsule orally. The results show that the peak
plasma concentration of omeprazole (Cmax) significantly decreased by 37.5% ± 13.3% in
CYP2C19*2/CYP2C19*2 or 3 and by 49.6% ± 20.7% in CYP2C19*1/CYP2C19*1; the area under the
concentration-time curve decreased by 37.9% ± 21.3% and 43.9% ± 23.7% in CYP2C19*2/CYP2C19*2 or 3 and
CYP2C19*1 /CYP2C19*1, respectively. Moreover, the Cmax and AUC of omeprazole sulfone increased by
160.3% ± 45.5% and by 136.6% ± 84.6%, 155.5% ±58.8% and 158.7% ±101.4% in CYP2C19*2/CYP2C19*2 or
3 and CYP2C19*1/CYP2C19*1, respectively. SJW increased the C (max) of 5-hydroxyomeprazole by
38.1%±30.5% and the AUC by 37.2% ± 26% in CYP2C19*1/CYP2C19*1 subjects, whereas it did not produce
any significant alterations to the corresponding pharmacokinetic parameters in CYP2C19*2/CYP2C19*2 or 3
subjects (Figure 1). The data suggest omeprazole and its metabolites all exhibit CYP2C19 genotype-dependent
pharmacokinetic profiles. SJW induces both CYP3A4 catalyzed sulfoxidation and CYP2C19 dependent
hydroxylation of omeprazole. Clinicians should be alert to other drugs catalyzed mainly by CYP2C19 such as
diazepam, chloroguanide hydrochloride, and mephenytoin to avoid possible clinically significant interactions with

                             Advances in Clinical Pharmacokinetics of Herbal Medicines

     It is reported that the multi drug transporter P-glycoprotein could also contribute to potential drug
interactions [17]. 22 healthy volunteers were randomized to either SJW 600 mg 3 times daily for 16 days or placebo.
It was found that P-glycoprotein expression increased 4.2 fold from baseline in subjects treated with SJW and
there was no effect with placebo, which suggests that increased P      -glycoprotein expression represent another
mechanism for the drug-herb interactions. However, study on the interaction between SJW and fexofenadine
showed a single dose of SJW resulted in a significant inhibition of intestinal P-glycoprotein even though
long-term treatment with SJW induced P-glycoprotein expression [18].
     CYP3A (CYP3A4 and CYP3A5) and MDR1 (P-glycoprotein) are induced through a common mechanism
involving the steroid X receptor/pregnane X receptor. The relative contributions of CYP3A and MDR1 to the
overall induction process were investigated [19]. In this study, selected in vivo probe drugs were administrated
before and after 12 days’treatment with SJW in 12 healthy subjects. Midazolam after oral and intravenous
administration was used to assess CYP3A activity in both the intestinal epithelium and the liver, whereas the
disposition of fexofenadine after an oral dose was assumed to be a measure of M        DR1 function, and the oral
plasma concentration-time profile of cyclosporine was considered to reflect both CYP3A and MDR1 activities.
The results showed that SJW markedly increase the drugs’clearance. With midazolam, the enhancement was
considerably less after intravenous administration (approximately 1.5-fold) than after oral administration
(approximately 2.7-fold), and estimated intestinal and hepatic extraction ratios were higher by approximately 1.2-
to 1.4-fold. By contrast, the oral clearances of fexofenadine and cyclosporine were equally increased by
approximately 1.6-fold and 1.9-fold, respectively. Although the extent of induction of CYP3A measured by
midazolam was apparently more than that of MDR1 measured by fexofenadine, with cyclosporine the change in
oral clearance appeared to be more closely associated with the increase in MDR1 rather than CYP3A. These
discordances indicate that the quantitative aspects of induction are complex and the extent of induction of a
particular drug is presently difficult to predict.
                                                        h/L             h/L               h/L
     SJW reduced the AUC of tacrolimus (306.9 ug· ± 175.8 ug· vs. 198.7 ug· ± 139.6 ug· and                h/L)
increased apparent oral clearance (349.0 ml/h/kg ± 126.0 ml/h/kg vs. 586.4 ml/h/kg ± 274.9 ml/h/kg). SJW
enhanced tacrolimus metabolism by inducing CYP3A and P-glycoprotein [20].
     The interaction between SJW and oral contraceptive was also reported [21]. It was found that SJW caused an
induction of ethinyl estradiol-norethindrone metabolism consistent with increased CYP3A activity.
     Subjects of clinical pharmacokinetic study of SJW also include patients. In a recent trial, ten stable renal
transplant patients received 600 mg SJW ext. for 14 days in addition to their regular regimen of tacrolimus (TAC)
and mycophenolic acid (MPA). It was found that administration of SJW extracts could result in a significant
decrease in AUC of TAC but didn’ affect MPA pharmacokinetics [22]. Another trial conducted on renal transplant
patients showed that SJW treatment resulted in a rapid and significant reduction of plasma cyclosporin A
concentrations and alterations in pharmacokinetics of some cyclosporin A metabolites [23]. Effects of SJW on
anticancer drug metabolism were also studied [24]. Five cancer patients were treated with irinotecan (a pro-drug of
SN-38) in the presence and absence of SJW. It was found that plasma levels of SN-38 were dramatically reduced
because SJW induced expression of the CYP3A4 isoform. Interactions of SJW extracts LI160 with amitriptyline
(an antidepressant) were investigated in twelve patients. Multiple-dose comedication with SJW extracts led to a
significant decrease in the AUC of amitriptyline by 22% and nortriptyline by 41%, as well as of all hydroxylated
metabolites, except for 10-E-hydroxynortriptyline [25].

                             Advances in Clinical Pharmacokinetics of Herbal Medicines

      As a derivative of SJW, pharmacokinetics safety, and antiviral effects of hypericin were studied in patients
with chronic hepatitis C virus infection. The first 12 patients received an 8-week course of 0.05 mg/kg of
hypericin and 7 patients received an 8-wk course of 0.10 mg/kg. The pharmacokinetics of hypericin was linear
and the elimination half-life was determined to be 36.1h and 33.8 h respectively. Considerable phototoxicity and
no significant anti-hepatitis C virus activity were observed [26].
      Recently, it was reported that 15 days of treatment with SJW on CYPs is not sufficient to cause a change in
plasma theophylline concentration. Twelve healthy male took an SJW caplet (300 mg) three times a day for 15
days. On day 14, they received a single oral dose of 400 mg of theophylline. SJW caused no significant changes in
the pharmacokinetics of theophylline in plasma, as well as its most metabolites in urine [27].
2. Gingko (Ginkgo biloba L.)
      Gingko preparations are derived from the leaves of Ginkgo biloba L., an ornamental tree dating back over
300 million years [28]. It has been used for the treatment of peripheral circulatory insufficiency, cerebrovascular
disorders, geriatric complaints and Alzheimer dementia. Most clinical studies have been conducted with a
standardized extract (EGb761) in solid oral dosage forms. EGb761 contain approximate 24% flavonoids (a
mixture of quercetin, kaempferol and isorhamnetin glycosides) and 6% terpenes (ginkgolides and bilobalides).
The structures of these compounds are shown in Figure 1. Adverse effects such as allergy have been reported and
related to ginkgolic acids [1].
      Clinical pharmacokinetic studies of ginkgolides A, B and bilobalide had been reported [29].15 healthy
volunteers were orally administered with free (Ginkgoselect®) or phospholipids (Ginkgoselect Phytosome®)
complex form. The Cmax and AUC of ginkgolides and bilibalides were about 2-3 fold higher when administrated
by the phospholipid complex (Table 1). In another trail of 10 healthy volunteers [30], pharmacokinetic parameters
of ginkgolide A and ginkgolide B were determined after intravenous administration, which were similar to those
reported in other literature.
      It was reported that different dosage regimens of G. biloba extract could affect pharmacokinetic parameters
of ginkgolide B [31]. Twelve healthy volunteers were randomly assigned to one of the two treatment groups: 40 mg
twice daily or 80 mg once daily. The results showed that a dosage of 40 mg twice daily was accompanied by a
significantly longer half-life and mean residence time (MRT) than a single 80 mg dose, even though the latter
caused a higher Cmax. The T max is 2.3 h after administration in both treatments.
      In a clinical study [15], midazolam, caffeine, chlorzoxazone and debrisoquin were administered to 12 healthy
subjects as substrates before and after 28 days administration of G. biloba to determine changes of CYP1A2,
CYP2D6, CYP2E1, and CYP3A4 activities. The results showed that G. biloba had little effects on CYP-mediated
drug metabolism.
      G. biloba hasn’ been reported to alter the pharmacokinetic parameter of other co-administered drugs.
Interaction between G. biloba and warfarin was negated by a clinical trial [32]. Concomitant use of G. biloba and
digoxin did not appear to have any significant effect on the pharmacokinetics of orally administered digoxin in
healthy volunteers too [33].
3. Garlic (Allium sativum L.)
      The potency of garlic (Allium sativum L.) has been acknowledged for more than 5000 years. In ancient times,
garlic was used as a remedy for i testinal disorders, flatulence, worms, respiratory infections, skin diseases,
wounds, symptoms of aging and many other ailments. Garlic products have experienced increasing popularity in
the last decade. According to a market research conducted in 1997, garlic products were the most popular dietary

                                Advances in Clinical Pharmacokinetics of Herbal Medicines

supplement used by U.S. households [34].
      The chemistry of garlic is quite complex and likely developed as a self-protective mechanism against
microorganisms and other insults. On average, a garlic bulb contains up to 0.9% -glutamylcysteines and up to
1.8% alliin. In addition to these main sulfur compounds, intact garlic bulbs also contain a small amount of
S-allylcysteine (SAC) which has been reported to contribute to the health benefits of some garlic preparations.
Garlic is famous for its characteristic odor, arising from allicin and other oil-soluble sulfur components. Typical
volatiles garlic essential oil include diallyl sulfide, diallyl disulfide, diallyl trisulfide, methyl allyl disulfide, methyl
allyl trisulfide, 2-vinyl-1,3-dithiin, 3-vinyl-1,2-dithiin and E,Z-ajoene [35].
      The pharmacokinetics of S-allylcysteine (SAC) was investigated after oral administration of garlic
supplement containing SAC to human volunteers [36]. Healthy volunteers (ages 38, 45, and 46) were given 500 mg
of aged garlic extract in capsule form. Their diets were controlled to eliminate consumption of the allium species
for 2 days before the test and 1 day after the test. It was found that T max of SAC was around 1 h after
administration and the half-life of SAC in humans after oral administration was more than 10 h.
      Effects of garlic extract on CYP450 2D6 and 3A4 activity in healthy volunteers were investigated [37]. Probe
substrates dextromethorphan (CYP2D6) and alprazolam (CYP3A4) were administered orally at baseline and again
after treatment with garlic extract (3 × 600 mg twice daily) for 14 days. The ratio of dextromethorphan to its
metabolite was 0.044 ± 0.48 at baseline and 0.052 ± 0.095 after garlic supplementation. There were no significant
differences between the baseline and garlic phases. For alprazolam, there were no significant differences in
pharmacokinetic parameters at bas eline and after garlic extract treatment (maximum concentration in plasma, 27.3
± 2.6 ng/mL versus 27.3 ± 4.8 ng/mL). The results indicate that garlic extracts are unlikely to alter the disposition
of coadministered medications primarily dependent on the C           YP2D6 or CYP3A4 pathway of metabolism. This
result was supported by another clinical study            . Probe-drug cocktails of midazolam, caffeine, chlorzoxazone,
and debrisoquin were administered before (baseline) and at the end of 28 days oral administration g                arlic oil to
determine changes of CYP1A2, CYP2D6, CYP2E1 and CYP3A4 activities. The results showed that Garlic oil
reduced CYP2E1 activity by 39% but didn’ affect CYP1A2, CYP2D6 and CYP3A4 activities significantly.
      However, different results were also reported. In one clinical study [39], the effect of garlic supplements on the
pharmacokinetics of saquinavir was investigated. Ten healthy volunteers received 10 doses of saquinavir at a
dosage of 1200 mg 3 times daily with meals for 4 days on study days 1 4, 22 25, and 36 39, and they received a
total of 41 doses of garlic caplets taken 2 times daily on study days 5 25. It was found that AUC decreased by
51% and Cmax decreased by 54% after 20 days administration of garlic caplets. After 10 days washout period, the
AUC and Cmax values returned to 60%-70% of their values at baseline. Another study with garlic supplements
devoid of allicin, for a period of 4 days, also indicated an insignificant (17%) decrease in the ritonavir AUC [40].
Ritonavir is both an inhibitor and inducer of CYP450 isozymes, so it i hard to assess the effects of garlic
supplements on CYP450 isozymes with a single dose ritonavir.
      The discordance among these studies was probably a result of the use of higher dose garlic supplements,
different garlic formulations or longer dosing period (20 days vs 14 days). Meanwhile, Saquinavir and ritonavir
not only are metabolized by CYP3A4 but also are substrates for P-glycoprotein. The pharmacokinetic changes of
saquinavir and ritonavir after garlic treatment may not be due to induction of CYP3A4 but other enzyme or
transporter such as P-glycoprotein. However, it is difficult to make a conclusion on the effects of garlic
supplements on CYP450 isozymes by now. Further investigation was required.
4. Siberian ginseng (Eleutheroccus senticosus)

                              Advances in Clinical Pharmacokinetics of Herbal Medicines

      Siberian ginseng (SG) is among the 10 most popular supplements used in the United States [41]. It is derived
from the roots of Eleutheroccus senticosus and is purported to behave as an “                     ,
                                                                                       adaptogen” a class of herbal
medications that confer resistance to the effects of stress. SG should not be confused with “Asian ginseng”         ,
which is derived from Panax ginseng, another genus and species in the Araliaceae family.
      Several active constituents have been isolated from the extract of SG. The constituents with reported
biological activities include eleutherosides, sesamin, hedarasaponin B, and isofraxidin as well as various
flavonoids and hydroxycinnamates. Most commercially available extracts have been standardized according to the
content of eleutheroside B and eleutheroside E.
      The effects of SG on CYP2D6 and CYP3A4 activity in normal volunteers were investigated [42]. Probe
substrates dextromethorphan (CYP2D6 activity) and alprazolam (CYP3A4 activity) were administered orally at
baseline and again following treatment with SG (485 mg twice daily) for 14 days. The results indicate that
standardized extracts of SG at generally recommended doses for over -the-counter use are unlikely to alter
CYP2D6 and CYP3A4 activity.
5. Goldenseal (Hydrastis Canadensis L.)
      Goldenseal, Hydrastis canadensis L., is a slow-growing, perennial herbaceous plant. In 1999, goldenseal
products had sales of $44 million, placing goldenseal among the 15 top-selling herbal supplements. Goldenseal
preparations are often used for the relief of cold and influenza symptoms and urinary tract infections because of
their antibacterial properties [43]. In clinical trials, goldenseal extract was found to ameliorate the primary IgM
response and improve immune activity [44]. Such studies prompted wide acceptance of goldenseal extract as an
alternative influenza remedy. It is believed that the bioactivity of goldenseal is due to the presence of the major
isoquinoline alkaloids berberine, hydrastine, canadine and palmatine.
      Extracts of H. canadensis have been reported to inhibit cytochrome P450 3A4. In experiments with 21
commercial ethanol extracts of popular herbal products, goldenseal rhizome extract was shown to have the highest
CYP3A4-inhibitory activity [45]. Recently, influence of goldenseal root on the disposition of the CYP3A4 substrate
indinavir in humans had been investigated [46]. A single 800 mg oral dose of indinavir was administered to healthy
volunteers before and after 14 days of treatment with goldenseal root (1140 mg twice daily). No statistically
significant differences in peak concentrations or oral clearance were observed. Half-life and time to reach peak
concentrations were also unchanged by goldenseal. It is unlikely that goldenseal root extracts alter
pharmacokinetics of indinavir in healthy adults.
6. Ephedra (Ephedra sinica)
      The Chinese herb ma huang is derived from the dried above-ground parts of Ephedra, most commonly
Ephedra sinica which is a natural source of several ephedrine alkaloids, including ephedrine, pseudoephedrine,
norephedrine, methylephedrine, norpseudoephedrine and methylpseudoephedrine [47]. The total alkaloid content of
E sinica is approximately 1% to 2%, with ephedrine being the most abundant alkaloid. Ephedrine and
pseudoephedrine together generally constitute more than 80% of the alkaloid content of the dried herb. Most
dietary supplements that contain ephedra are marketed for weight loss. However, a number of reports of serious
cardiovascular toxicity have been reported in persons taking dietary supplements that contain ma huang (Ephedra
sinica). Adverse events have included psychosis, ischemic and hemorrhagic stroke, seizures, acute myocardial
infarction, myocarditis, and sudden death [48].
      It has been reported that the pharmacokinetics of ephedrine in the form of ephedra extracts is similar to those
of synthetic ephedrine [38]. Recently, pharmacokinetics of ephedra alkaloids and caffeine after single-dose dietary

                              Advances in Clinical Pharmacokinetics of Herbal Medicines

supplement was investigated [49]. Eight healthy adults received a single oral dose of a thermogenic dietary
supplement containing 17.3mg ephedrine 5.3mg pseudoephedrine and 175 mg caffeine. Serial plasma and urine
samples were analyzed by use of liqid chromatography-tandem mass spectrometry method. The pharmacokinetic
parameters are shown in Table 2, which are in close agreement with values reported in previous studies. A
prolonged half-life of ephedrine and pseudoephedrine was observed in one subject with the highest urine pH. It
suggests the pH dependence of renal elimination of the ephedrine alkaloids which could lead to undesirable side
effects in persons with urine high pH values.
7. Echinacea (Echinacea purpurea root)
     Echinacea purpurea, also known as the purple coneflower, is an herbal medicine with positive effects on
various immune parameters. The most widely used herbal product in the United States is a liquid extract made
from the root of Echinacea purpurea. It is usually used in supportive therapy of colds and chronic infections of
the respiratory and the lower urinary tract. Many compounds were so far isolated and characterized from the roots
or top parts of the plant. These included alkylamides, polyphenolic caffeic acid derivatives, polysaccharides,
alkaloids, essential oils and many other miscellaneous structures [50]. The alkylamides and caffeoyl-phenols are
commonly used as markers to determine the medicinal quality of plant material and herbal extracts.
     Recently, the effects of echinacea on CYP activity in healthy adults were assessed by Gorski [51] using the
CYP probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), dextromethorphan (CYP2D6), and midazolam
(hepatic and intestinal CYP3A). Caffeine, tolbutamide, dextromethorphan, and oral and intravenous midazolam
were administered before and after a short course of echinacea (400 mg 4 times a day for 8 days ). The results
showed that echinacea significantly reduced the oral clearance of substrates of CYP1A2 (caffeine). The oral
clearance of substrates of CYP2C9 (tolbutamide) was reduced by 11%, but this change was not considered to be
clinically relevant because the 90% CIs were within the 80% to 125% range. The oral clearance of
dextromethorphan in 11 CYP2D6 extensive metabolizers was not affected by echinacea dosing. Gorski also
reported the effects of echinacea administration on CYP3A4 activity. Echinacea a           dministration significantly
increased the systemic clearance of midazolam by 34% and significantly reduced the midazolam area under the
concentration-time curve by 23%. In contrast, the oral clearance of midazolam was not significantly altered and
the oral availability of midazolam after echinacea dosing was significantly increased. However, hepatic
availability and intestinal availability significantly altered in opposite directions, which suggest that the type of
drug interaction between echinacea and other CYP3A substrates will be dependent on the relative extraction of
drugs at hepatic and intestinal sites.
8. Annual wormwood (Artemisia annua L.)
     The plant Artemisia annua L. has been used in China for more than 2000 years to treat fevers. The current
pharmacopoeia of the People's Republic of China describes the dried herb of A. annua L. as a remedy for fevers
including malaria. The active principle of A. annua L. is artemisinin, an endoperoxide sesquiterpene lactone,
mainly in its leaves and inflorescences.
     Recently, Pharmacokinetics of artemisinin was studied in healthy volunteers received one liter of tea
preparation from nine grams of Artemisia annua leaves, which contains 94.5 mg of artemisinin. The maximum
plasma concentration of artemisinin was 240 ± 75 ng/mL and the area under the plasma concentration-time curve
was 336±71 ng/ml· Artemisinin was absorbed faster from herbal tea preparations than from oral solid dosage
forms but bioavailability was similar [52].
9. Horse chestnut (Aesculus hippocastanum L.)

                              Advances in Clinical Pharmacokinetics of Herbal Medicines

       Horse chestnuts are the fruits of horse chestnut tree growing in Asia and north Greece. A number of products
have been isolated from the chestnut seeds: bioflavonoids such as quercetin, kaempherol and their diglycosyl
derivatives, as well as anti-oxidants, such as proanthocianidin A2 and the coumarins esculin and fraxin. The active
components are considered to be a mixture of triterpenic saponins called escin, accumulated in seeds. Escin is
comprised of a-escin and ß      -escin fractions and ß-escin is the active component in the mixture. Because of its
anti-inflammatory, venotonic properties and anti-oedematous properties, and because of its high degree of
tolerability, escin is largely employed in the therapy of chronic venous insufficiency.
       Bioavailability of beta-aescin in two different preparations has been investigated in clinical studies [53]. The
results showed that there was no significant difference in pharmacokinetic parameters of escin in a retarded
formulation and a non-retarded formulation.
10. Milk thistle (Silybum marianum L.)
       Milk thistle is one of the most commonly used herbal medicines. The annual sale of this product is about
US$180 million in Germany. A standardized extract of milk thistle contains at least 70% silymarin. Silymarin is a
mixture of flavonolignans extracted from the seeds of milk thistle and is used traditionally as a heptoprotective
agent. Previous studies have revealed that silymarin is composed of silybin, isosilybin, silychristin, silydianin, and
other phenolic compounds [54].
       Silymarin was reported to protect the liver against CCl4, acetaminophen, amanitin, thioacetamide, and
D-galactosamine-mediated hepatotoxicity in rats [55]. Silymarin had also been reported to inhibit certain hepatic
enzymes such as aminopyrine demethylase, benzopyrene hydroxylase and ethoxy coumarin O-deethylase in rats
     . Treatment with silymarin also significantly reduced the activity of CYP3A4 enzyme and uridine
diphosphoglucuronosyl transferase in human hepatocyte cultures [57].
       The studies on interactions between milk thistle and indinavir have been reported [58]. The volunteers took 4
doses of indinavir 800 mg every 8 h on an empty stomach for baseline pharmacokinetics. This dosing and
sampling were repeated with silymarin after the subjects took 160 mg silymarin 3 times each day for 13 days.
When given alone and combined with silymarin, the geometric mean indinavir area under the plasma
concentration-time curve was 20.7 h·       mg/L and 19.4 h·   mg/L respectively. It suggested that silymarin had no
apparent effect on indinavir plasma concentrations. The results were supported by another clinical trial of milk
thistle and indinavir [59].
11. Saw palmetto (Serenoa repens)
       Saw palmetto (Serenoa repens) is derived from the berry of the American dwarf palm tree found in many
areas of the southeastern United States. It is currently the fifth highest-selling herbal product in the United States
     . It is the most popular herbal product used for the treatment of symptoms related to benign prostatic
hyperplasia. The major constituents in extract of Saw palmetto are nonesterified fatty acids and phytosterols such
as oleic acid, lauric acid, palmitic acid, linoleic acid and -sitosterol [42].
      The effects of Saw palmetto extracts on activity of CYP2D6 and CYP3A4 have been studied [61]. In this
clinical trial, the probe substrates dextromethorphan (CYP2D6 activity) and alprazolam (CYP3A4 activity) were
administered orally at baseline and again after exposure to saw palmetto (320 mg capsule once daily) for 14 days.
Dextromethorphan metabolic ratios and alprazolam pharmacokinetics were detected to determine the changes of
CYP2D6 and CYP3A4 activity. The results indicated that extracts of saw palmetto at generally recommended
doses were unlikely to alter the disposition of coadministered medications primarily dependent on the CYP2D6 or
CYP3A4 pathways for elimination.

                               Advances in Clinical Pharmacokinetics of Herbal Medicines

12. Wood creosote
     Wood creosote is herbal over -the-counter medication that has been used as antidiarrheal and agent under the
brand name Seirogan. Approximately 1.16 billion Seirogan pills (wood creosote 45mg per pill) are sold worldwide
annually. Wood creosote is a mixture of simple phenolic compounds including guaiacol, creosol, o              -cresol and
4-ethylguaiacol as major active components. Wood creosote has been shown to have antidiarrheal activities including
suppressing gastrointestinal mobility, slowing intestinal transit time, inhibiting chloride ion secretion and augmenting
fluid adsorption from the intestine in animal models. The most common adverse effects of wood creosote are mild
headache and dizziness. There are no known drug-drug interactions with wood creosote [62].
      It was reported that dose-escalation safety and pharmacokinetics of wood creosote had been investigated [63].
Healthy subjects randomly received escalating single doses of wood creosote (45, 90, 135, 180, and 225 mg) and
placebo. Pharmacokinetics of active components (guaiacol, creosol, o         -cresol, and 4 -ethylguaiacol) was studied.
Area under the conc entration-time curve increased in a dose-proportional manner for total guaiacol, creosol, and
o-cresol. No apparent differences by sex were noted for any of the four active components. Also, the doses of
wood creosote were rapidly absorbed, conjugated, and eliminated.
13. Thymus oil (Thymus vulgaris L.)
      Thymus oil is derived from thyme (Thymus vulgaris L.), which is popular for respiratory disorders and there
is good evidence on their efficacy. Thymus oil has shown clinical efficacy against chronic and acute bronchitis.
Other pharmacological activities such as anti-inflammatory, antimicrobial, antiviral and antioxidant effects were
also reported [59]. Thyme essential oil was characterized by the presence of ?-terpinene (4.3%), p-cymene (23.5%),
carvacrol (2.2%), and thymol (63.6%), which composed 93.6% of the total oil [64].
      Recently, study on Systemic availability and pharmacokinetics of thymol in humans was reported [65].
Healthy subjects received a single dose of a Bronchipret TP tablet, which contain 1.08 mg thymol. No thymol
could be detected in plasma or urine. However, the metabolites thymol sulfate and thymol glucuronide were
found in urine and identified by LC-MS/MS. Plasma and urine samples were analyzed after enzymic hydrolysis of
the metabolites by headspace solid-phase microextraction prior to GC analysis and flame ionization detection.
Thymol sulfate, but not thymol glucuronide, was detectable in plasma. Peak plasma concentrations were 93.1 ±
24.5 ng/ml and were reached after 2.0 ±0.8 h. The mean terminal elimination half-life was 10.2 h. Thymol sulfate
was detectable up to 41 h after administration. Urinary excretion could be followed over 24 h. The combined
amount of both thymol sulfate and glucuronide excreted in 24-h urine was 16.2%± 4.5% of the dose.


     Herbal medicines were always administrated as dietary supplements and exempted from regulatory drug
evaluation that is obligatory for conventional medicines in most countries such as US. However, with growing
recognition of adverse effects and even toxicity of herbal medicines, it is becoming necessary to establish a
special licensing policy for herbal medicines that improves their quality and safety without imposing an
unbearable burden on the manufacturer. A registration process reviewing quality, safety and efficacy of herbal
medicinal products is established in certain European countries and the FDA is considering reviewing certain
botanicals via the IND/NDA (Investigational New Drug/New Drug Application) process [66]. Determination of
herbal pharmacokinetics and evaluation of drug interaction can promote more rational use of herbal products. As
can be seen in the review, more and more studies on clinical pharmacokinetics and drug interactions of herbal

                                   Advances in Clinical Pharmacokinetics of Herbal Medicines

medicines were conducted since 2001. Due to complex composition herbal medicines and limited knowledge of
active constituents, most clinical studies were focused on several popular herbs such as St John’ Wort and only
limited active constitutes are involved in pharmacokinetic study. With advances in instrumentation like
HPLC/MS/MS and HPLC/MS/NMR, an increasing number of components are being identify and quantified
which can promote the clinical pharmacokinetic study of herbal medicines. In summary, much more work is
needed to determine clinical pharmacokinetics and drug interactions of herbal medicines.

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                                                                   (Edited by Joesmile, Jane Chen, Qingju Mao, Xin Wang)

                                   Advances in Clinical Pharmacokinetics of Herbal Medicines

                            Table 1 Human pharmacokinetic parameters of ginkgolides and bilobalide
     Compounds     Ginkgo-lideA   Ginkgo-lideB    Biloba-lide   Ginkgo-lideA Ginkgo-lideB Biloba-lide   Ginkgo-lideA    Ginkgo-lideB
Subject           Humans          Humans         Humans         Humans       Humans       Humans        Humans         Humans
N                 15              15             15             15           15           15            10             10
Application       Oral1           Oral1          Oral1          Oral2        Oral2        Oral2         i.v.           i.v.
Dose(mg)          160             160            160            160          160          160           4.083          --
Cmax(ng/ml)       41.8± 14        5.6± 2.2       37.6± 14.2     108± 8       13.4± 2.2    60.3± 13      --             --
T max (h)         2               2              2              4            3            3             1              1
T1/2 ß(h)         2.63± 0.45      2.34± 0.38     2.30± 0.24     1.88± 0.13   1.69± 0.3    3.16± 0.3     3.75± 0.25     4.25± 0.32
AUC               8434±3009       1030±447       6927±2850      28361± 768   2531± 287    13962± 1948   68305± 2766    19714± 1067
Reference         [29]                                          [29]                                    [30]

   after administration 160mg Ginkgoselect® formulation (24% flavonoids and 6% terpenes in free form);
   after administration 160mg Ginkgoselect® Phytosome formulation(24% flavonoids and 6% terpenes in phospholipid complex);
   after intravenous administration 40ml injection containing Ginkgolide A 0.102mg/ml.

                 Table 2 Human pharmacokinetic parameters of ephedrine, pseudoephedrine and caffeine
      Compounds      dosage       tmax        Cmax        t1/2      AUC           CL/F            V/F                          CLR
                      mg        (min)       (ng/mL)       (h)     (ng *h/mL)   (L/h* kg)       L/kg                       (L/h* kg)
 Ephedrine        17.3      142.5± 61.6 63.5±11.2   6.06± 1.26  759.4±189.6   0.35± 0.07    2.35± 0.38                     0.21±0.07
 Pseudoephedrine   5.3     146.3± 58.8   24.1±3.5    6.26± 1.62  287.3± 60.1 0.28±0.05       2.5± 0.52                    0.22±0.06
 Caffeine          175        94± 29.7    5.0± 1.26   8.1± 4.76   73.7± 43    0.81±0.46     0.44± 0.07                        --

                   Fig. 1   Concentration-time curves of 5-hydroxyomeprazole in different CYP2C19 subjects


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