Extract
Note: Please read the complete
full text with Figures and Tables at
Introduction
Yin Zhi Huang (YZH), a decoction of Yin Chin
(Artemisia capillaris) and 3 other herbs, is widely used in Asia to
prevent and treat jaundice[1_3]. Recently, Huang
et al demonstrated that YZH activated the constitutive androstane
receptor (CAR, NR1I3), a key regulator of bilirubin clearance
in the liver[4_6]. CAR leads to the increased expression of
several CYP450 enzymes, including cytochrome P450 (CYP)
3A4 and CYP2C19[7,8]. Therefore, we suppose that YZH may
be a modulator of CAR-targeted CYP450 isoenzymes. As a
result, in clinical situations, herb-drug interactions may
occur between YZH and substrate drugs of these CYP450
enzymes.
Omeprazole is a well-known CYP2C19 substrate which
undergoes hydroxylation to form its major metabolite
5-hydroxyomeprazole. CYP3A4 mediates the sulfoxidation
of omeprazole to form the second major metabolite omeprazole sulfone. CYP2C19 is a genetic polymorphism
enzyme. A person exhibits either extensive or poor
CYP2C19 enzyme activity. The latter phenotype occurs in
1%_3% of Caucasians and 13%_23% of
Asians[9]. The most common
CYP2C19 allelic variants causing the poor
meta-bolizer (PM) phenotype contain a splicing defect
(CYP2C19*2) or premature stop codon
(CYP2C19*3)[10]. The polymorphism of CYP2C19 was reported to exhibit a
marked effect on the pharmacokinetics of
omeprazole[11].
The pharmacokinetics of omeprazole is also prone to be
affected by CYP450 inducers, such as
rifampicin[12,13] and some herbal medicines like St John's wort and
Ginkgo-biloba[14,15].
Until now, the effects of YZH on CYP450 subtypes and
their clinical significance have still not been determined;
herb_drug interactions for this herbal remedy are generally
not known or are poorly studied. Thus, we carried out the
present study to observe the impacts of YZH on CYP2C19
and CYP3A4 enzyme activities, and the potential herb-drug
interaction involving YZH and omeprazole related to
different CYP2C19 genotypes.
Materials and methods
Drugs and reagents YZH oral liquid was purchased from
Shuang He (Beijing, China, No 272044). Omeprazole,
5-hydroxyomeprazole, and omeprazole sulfone were
generous gifts from Jae-Gook SHIN (Inje Univ College of
Medicine, Gaegum-dong, Busanjin-gu, Busan, Korea), and
HPLC-grade solvents were obtained from Hunan Chemical Institute (Changsha, China).
Patients Eighteen unrelated, healthy adult men, from a
total of 110 healthy Chinese volunteers, who had been
screened for the CYP2C19 genotype, were recruited for this
study (6 CYP2C19*1/CYP2C19*1, 5
CYP2C19*1/*2, 1 CYP2C19*1/*3, and 6
CYP2C19*2/CYP2C19*2). Genotyping procedures for identifying CYP2C19 wild-type
gene (CYP2C19*1) and the 2 mutated alleles,
CYP2C19*2 in exon 5 and CYP2C19*3 in exon 4, were performed by the
PCR_restriction fragment length polymorphism method as
described previously[9]. This study was approved by the
Ethics Committee Board of Central South University, Hunan,
China. The patients gave written informed consent to
participate. All of the patients finished the entire protocol of
this study. The participants were required between the ages
of 18 and 28 years, non-smokers, and have a standard body
mass index between 18 and 30 kg/m2. The patients were
healthy with no clinically relevant conditions identified
from medical history, physical examinations,
electro-cardiogram, and routine laboratory tests (blood chemistry,
hematology, and urine analysis). All the patients were
refrained from use of any prescription or non-prescription
medication 2 weeks before and throughout the study. They
were also abstained from grapefruit juice, herbal dietary
supplements, and caffeine-containing beverages, including
coffee and green tea, 2 weeks before the study and during
the study period. The volunteers were served standard meals
and were monitored during the experimental period for the
development of any possible adverse effects.
Study design and clinical protocol The study was
carried out in a 2-phase crossover manner with a 5 week
washout period between phases. In each phase, 18 volunteers
received placebo or YZH oral liquid 10 mL 3 times daily for 14
d. On the 15th day, all the patients were given a single oral
dose of omeprazole (20 mg capsule) with 250 mL of warm
water, after an overnight fast. Two to four hours later, they
had access to water and received breakfast. Omeprazole
was given at 8:00 h, and 5 mL blood samples were collected
into heparinized tubes from the antecubital vein immediately
before (0 min) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10,
and 12 h after drug administration. Blood samples were
centrifuged at 2000×g for 10 min, and plasma was separated and
stored at -80 °C until analyzed.
Analytic method of omeprazole and its metabolites
Plasma concentrations of omeprazole and its metabolites,
5-hydroxyomeprazole and omeprazole sulfone, were
quantified by validated HPLC with UV detection at a wavelength
of 302 nm according to the method previously
described[14] with minor modifications. The HPLC system (SHIMADZU
2010C HPLC series, Kyoto, Japan) was composed of a
solvent-delivery system, an online degasser, an automatic
sample injector, and a variable-wavelength detector. The
data analysis included Class VP systems. In brief, a mixture
of 1000 µL of a plasma aliquot and 100 µL propranolol (internal
standard) were extracted with 5 mL dichloromethane. Each
tube was blended in a vortex mixer vigorously for 3 min and
centrifuged at 2500×g for 10 min. The organic layer was
decanted and evaporated to dryness under nitrogen. The
residue was reconstituted with 100 µL of the mobile phase,
and 20 µL of this solution was injected into an HPLC column.
A Hypersil BDS C18 column (particle size, 5 µm; 4.6 mm×200
mm; Thermo Co, Phenomenex, US) was used as an analytic
column. The mobile phase was a mixture of 10 mmol/L
ammonium formate (pH 4), methanol, and acetonitrile (60:25:15,
v/v/v). The average recoveries of omeprazole,
5-hydroxy-omeprazole, omeprazole sulfone, and the internal standard
were 89%, 73%, 87%, and 85%, respectively. The interday
coefficients of variation for omeprazole,
5-hydroxy-omeprazole, and omeprazole sulfone were 5.1%, 5%, and
10%, respectively, indicating high reproducibility. The
validated limit of quantification was 2.656 ng/mL for omeprazole.
The retention times were 5.25, 8.69, 9.86, and 11.52 min for
the internal standard, 5-hydroxy-omeprazole, omeprazole
sulfone, and omeprazole, respectively, and the flow rate was
1 mL/min.
Analytic method of YZH components The
concentrations of 4 main components in YZH oral liquid baicalin,
geniposide, chlorogenic acid, and 6,7-dimethylesculetin
(scoparone) were quantified by validated HPLC with UV
detection at a wavelength of 276, 230, 335, and 280 nm,
respectively, according to the method previously
described[29_32] with minor modifications. The HPLC system (Agilent 1100
series, Agilent Co, California, USA) was composed of a
solvent-delivery system, an online degasser, an automatic
sample injector, and a variable-wavelength detector. The
data systems included a HP Chem Station controller
(Hewlett-Packard, Houston, Florida, USA). A ZORBAX Eclipse
XDB-C18 column (particle size, 5 µm; 4.6×150 mm; Agilent,
California, USA) was used as an analytic column. The
mobile phase was a mixture of 0.625% acetic acid and
acetonitrile (85:15, v/v) for chlorogenic acid, 0.625% acetic acid and
methanol (75:25, v/v) for 6,7-dimethylesculetin, 0.625%
acetic acid and acetonitrile (75:25, v/v) for baicalin, and a mixture
of distilled water and acetonitrile (80:20,
v/v) for geniposide. The average recoveries of baicalin, geniposide, chlorogenic
acid, and 6,7-dimethylesculetin were 100.1%, 100.15%,
93.6%, and 97.27%, respectively. The interday coefficients
of variation for baicalin, geniposide, chlorogenic acid, and
6,7-dimethylesculetin were 1.66%, 1.63%, 3.5%, and
1.96%, respectively, indicating high reproducibility.
Pharmacokinetic analysis The area under the plasma
concentration-time curves (AUC) of omeprazole and its
metabolites were calculated by the linear trapezoidal method
and further extrapolated to infinity by dividing the last
experimental concentration by the terminal slope
(l). The terminal elimination rate constant (l) was determined by
loglinear regression, and the terminal elimination half-life
(T1/2) was determined by the following relationship:
T1/2=0.693/l. The peak plasma concentration
(Cmax) and time to peak concentration
(tmax) were assigned by visual
inspection of the data. The AUC from time 0 to infinity
(0_∞) ratios of omeprazole to 5-hydroxyomeprazole
(AUCOPZ/AUCOH-OPZ)
and omeprazole to omeprazole sulfone
(AUCOPZ/AUCOPZ-SUL) were calculated as the apparent markers of CYP2C19 and
CYP3A4 activities,
respectively[14,16,17].
Statistical analysis The pharmacokinetic parameters of
omeprazole and its metabolites treated by placebo and YZH
were analyzed using the paired Student's t-test. The mean
changes in pharmacokinetic parameters among the 3 CYP2C19
genotype groups were compared, using one-way ANOVA.
P<0.05 was considered statistically significant for all tests.
All statistical analyses were performed using SPSS software
(version 11.0, SPSS, Chicago, IL, USA). Data are expressed
as mean±SEM.
Results
YZH components analysis Qualitative and quantitative
measurement by HPLC of 4 components of YZH including
baicalin, chlorogenic acid, 6,7-dimethylesculetin, and
geniposide are presented in Figure 1. In every 10 mL YZH
oral liquid, there is 442.49±75.38 mg 6,7-dimethyles-culetin,
29.7±5.64 g baicalin, 39.64±0.002 mg geniposide, and
476.22±58.16 mg chlorogenic acid.
Plasma omeprazole pharmacokinetics The mean
pharmacokinetic parameters of omeprazole and its metabolites
after 14 d of treatment by placebo and YZH are summarized
in Table 1. After YZH administration, the plasma
concentrations of omeprazole significantly decreased in comparison
to the control (placebo; Figure 2A). The
Cmax decreased by 38.84%±25.72%
(P=0.030), 30.33%±18.22% (P=0.019), and
15.69%±5.18% (P=0.001) in the
CYP2C19*1/CYP2C19*1,
CYP2C19*1/CYP2C19*2 or *3 and
CYP2C19*2/CYP2C19*2 patients, respectively; the
AUC(0_∞) of omeprazole decreased by 46.69%±17.82%
(P=0.007),
41.38%±14.04% (P=0.002), and 16.25%±12.18%
(P=0.039) in CYP2C19*1/CYP2C19*1,
CYP2C19*1/CYP2C19*2 or *3 and
CYP2C19*2/CYP2C19*2 patients, respectively. No
significant difference in tmax was observed for omeprazole
between the placebo and YZH treatment phases.
Plasma pharmacokinetics of omeprazole metabolites
YZH greatly increased the plasma concentrations of
5-hydroxyomeprazole and omeprazole sulfone (Figure 2B, 2C).
The Cmax and AUC(0_∞)
of 5-hydroxyomeprazole increased by 81.43%±41.54%
(P=0.001), 54.11%±33.57% (P=0.001),
42.82%±16.83% (P=0.001), 49.56%±46.79%
(P=0.027),
31.93%±22.97% (P=0.012), and 40.07%±33.56%
(P=0.024) in CYP2C19*1/CYP2C19*1,
CYP2C19*1/CYP2C19*2 or *3 and
CYP2C19*2/CYP2C19*2 patients, respectively,whereas the
Cmax and
AUC(0_∞) of omeprazole sulfone
increased by 73.25%±31.09% (P=0.002), 57.44%±30.33%
(P=0.000), 45.25%±41.27% (P=0.026), 40.14%±39.36%
(P<0.05), 22.54%±15.81% (P=0.012), and 59.92%±36.69%
(P=0.007) in CYP2C19*1/CYP2C19*1,
CYP2C19*1/CYP2C19*2 or *3 and
CYP2C19*2/CYP2C19*2 patients, respectively.
Omeprazole hydroxylase activity Based on the changes
in the omeprazole and 5-hydroxyomeprazole plasma concentrations, the
AUCOPZ/AUCOH_OPZ ratios (an index of
omeprazole hydroxylase activity) decreased by
64.80%±12.51% (P=0.001), 57.98±14.80%
(P=0.002), and
37.74%±16.07% (P=0.004) in
CYP2C19*1/CYP2C19*1,
CYP2C19*1/CYP2C19*2 or *3 and
CYP2C19*2/CYP2C19*2 patients, respectively (Figure 3A). The
decrease in the
AUCOPZ/AUCOH_OPZ ratio was significantly
greater in CYP2C19*1/CYP2C19*1 and
CYP2C19*1/CYP2C19*2 or *3 groups than those in the
CYP2C19*2/CYP2C19*2 group (P=0.047 or 0.009, Figure 3A).
Omeprazole sulfoxidation activity The
AUCOPZ/AUCOPZ_SUL ratios (an index of omeprazole sulfoxidation activity) also
significantly decreased after YZH administration by
63.31%±18.45% (P=0.004), 54.87%±18.42%
(P=0.003), and 45.16%±15.54% (P=0.003) in the
CYP2C19*1/CYP2C19*1,
CYP2C19*1/CYP2C19*2 or *3 and
CYP2C19*2/CYP2C19*2 patients, respectively (Figure 3B). No
significance was observed in the change degrees of the
AUCOPZ/ AUCOPZ_SUL ratio among the 3 2C19 genotypes
(P>0.05, Figure 3B).
Discussion
Since there may be variability in the YZH products
currently on the market[18], in order to be better controlled, the
YZH oral liquid used in our study was of the same batch
number. Moreover, we quantified 4 main components of
YZH oral liquid using HPLC with UV detection, which might
help explain the results and conclusions extrapolated from
our study in some ways. Baicalin accounts for 97.69% for
every 10 mL YZH oral liquid used in our experiment, which is
in agreement with the manufacture standard of YZH to
contain above 90% baicalin.
Because the first and last time points of quantifiable
concentrations for the 3 analytic compounds varied among
individuals, and to keep the data comparable, we analyzed
data by using AUC(0_∞).
In this study, we demonstrate that YZH significantly
induces the CYP2C19-dependent omeprazole hydroxylation.
We use the AUC ratio of omeprazole to 5-hydroxyomeprazole
to evaluate the phenotypic activity of omeprazole hydroxylation, which is recognized to be a valid
representation of the hydroxylation phenotype
activity[14,17]. Moreover, a recent study indicated that
AUCOPZ/AUCOH_OPZ was likely to be a more reliable and sensitive method for probing
CYP2C19 than those previously used[9]. In this study, we
show that YZH treatment caused a 16.08%_79.36% decrease in
AUCOPZ/AUCOH_OPZ. The change percentage of
AUCOPZ/AUCOH_OPZ following YZH administration in
CYP2C19*1/CYP2C19*1 and
CYP2C19*1/CYP2C19*2 or *3 are 1.5 and 1.7 times greater than that of
CYP2C19*2/CYP2C19*2, respectively, exhibiting a
gene-dosage-inductive effect of YZH on CYP2C19 activity. In our current
study, CYP2C19 *2 homozygotes display a large degree of
induction. Nevertheless, PM have no or low CYP2C19
activity, and thus would not be expected to be markedly
induced[12]. Two possible explanations for this discrepancy
are that CYP2C19 still has some level of activity in the
PM with *2 mutation and thus can be induced, or the
induced hydroxylation is catalyzed by a non-CYP2C19
hydroxylase[13,14].
We also observed a potent inductive action of YZH on
the CYP3A4-mediated metabolic pathway of omeprazole
sulfoxidation. YZH treatment produced a marked decrease
in the AUCOPZ/AUCOPZ_SUL ratios of all the patients,
indicating that YZH is also a potential in
vivo inducer of CYP3A4.
The effects of the components of YZH on CYP450 have
previously been studied. Baicalin could induce several
CYP450 in rat liver microsomes[19], while chlorogenic acid
has no obvious effects on CYP450[20]. Due to a high
concentration of baicalin in YZH oral liquid, the inductive effect of
baicalin on CYP3A4 and CYP2C19 might be one of the
mechanisms for our study. Moreover, the nuclear receptor CAR
is involved in molecular mechanisms of CYP450
induction by binding to the promoters of both CYP2C19 and
CYP3A4[7,8]. Therefore, 6,7-dimethylesculetin, an agonist
for CAR, according to Huang et
al[4], might increase CYP2C19 and CYP3A4 expression in the mRNA level and
further increases CYP2C19 and CYP3A4 enzyme activities,
which also helps explain the results of our study. Similarly,
rifampin and St John's wort induce CYP450 enzymes and
interact with other drugs in clinical situations by activating
another nuclear receptor, the pregnane X
receptor[21,22]. Since CAR transcriptionally regulates the expression of other
CYP450 subtypes, such as CYP2B6 and
CYP2C9[23_25], the relationships between YZH and other CYP450 enzymes are
worth further exploration.
As we mentioned earlier, like other herbal remedies, YZH
contains many components which may affect various drug
metabolic enzymes, drug transporters, and
receptors[4_6,20]. Thus, herb-drug interactions are likely to be more
complicated than drug-drug interactions. Herbal medicine St John's
wort was reported to exert a biphasic effect on CYP enzymes
starting with a parent inhibition followed by a significant
induction during long-term use due to its enzyme inhibiting-,
expression inducing-, and drug transport-promoting
properties[26,27]. However, we do not know whether or not YZH
affects the activities of the 2 enzymes in a similar way.
In this study, YZH use caused more than a 15% of
decrease in the Cmax and
AUC(0_∞) of omeprazole. YZH is beginning to be taken as herbal tea by people around the
world[26], and our current study emphasized that clinicians
should be alert to other drugs catalyzed mainly by
CYP2C19[27], such as the protease inhibitor nelfinavir, tricyclic
antidepressants (imipramine, amitriptyline, and clomipramine),
benzodiazepines (diazepam and flunitrazepam), proguanil and
other proton pump inhibitors (lansoprazole and pantoprazole), and those catalyzed mainly by
CYP3A4[28] to avoid possible clinically significant interactions with YZH.
It takes time to arouse the attention of people to the adverse
effects of a drug, especially for traditional Chinese medicine
(TCM). However, with more and more adverse effects of
TCM occurring[29], it is urgent for clinical pharmacologists
to guide people to take TCM more safely and effectively.
In conclusion, YZH, acting as an inducer of both CYP3A4
and CYP2C19, increases the metabolism of omeprazole in a
CYP2C19 genotype-dependent manner and results in
decreased plasma omeprazole concentrations. Attention should
be paid for clinicians to avoid related drug interactions when
YZH is co-administrated with CYP2C19 and CYP3A4
substrate drugs like omeprazole.
References
1 Yin J, Wennberg RP, Xia YC, Liu JW, Zhou HZ. Effect of a
traditional Chinese medicine, yin zhi huang, on bilirubin
clearance and conjugation. Dev Pharmacol Ther 1991; 16: 59_64.
2 Yin J, Wennberg RP, Miller M. Induction of hepatic bilirubin and
drug metabolizing enzymes by individual herbs present in the
traditional Chinese medicine, yin zhi huang. Dev Pharmacol
Ther 1993; 20: 186_94.
3 Dong YS, Huang ZH, Wu LF. Treatment of infantile hepatitis
syndrome with injection of yin zhi huang. Zhongguo Zhong Xi
Yi Jie He Za Zhi 1992; 12: 26-7, 5_6.
4 Huang WD, Zhang J, Moore DD. A traditional herbal medicine
enhances bilirubin clearance by activating the nuclear receptor
CAR. J Clin Invest 2004; 113: 137_43.
5 Huang W, Zhang J, Chua SS, Qatanani M, Han Y, Granata R,
et al. Induction of bilirubin clearance by the constitutive
androstane receptor (CAR). Proc Natl Acad Sci USA 2003; 100:
4156_61.
6 Xie W, Yeuh MF, Radominska-Pandya A, Saini SP, Negishi Y,
Bottroff BS, et al. Control of steroid, heme, and carcinogen
metabolism by nuclear pregnane X receptor and constitutive
androstane receptor. Proc Natl Acad Sci USA 2003; 100: 4150_5.
7 Goodwin B, Hodgson E, D'costa JD, Liddle C. Transcriptional
regulation of the human CYP3A4 gene by the constitutive
androstane receptor. Mol Pharmacol 2002; 62: 359_65.
8 Chen YP, Ferguson SS, Goldstein JA. Identification of
constitutive androstane receptor and glucocorticoid receptor binding sites
in the CYP2C19 promoter. Mol Pharmacol 2003; 64: 316_24.
9 de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer
UA, Goldstein JA. The major genetic defect responsible for the
polymorphism of S-mephenytoin metabolism in humans. J Biol
Chem 1994; 269: 15 419_22.
10 Brosen K, de Morais SM, Meyer UA, Goldstein JA. A
multifamily study on the relationship between CYP2C19 genotype and
S-mephenytoin oxidation phenotype. Pharmacogenetics 1995; 5:
312_7.
11 Chang M, Tybring G, Dahl ML, Gotharson E, Sagar M, Seensalu
R, et al. Interphenotype differences in disposition and effect on
gastrin levels of omeprazole-suitability of omeprazole as a probe
for CYP2C19. Br J Clin Pharmacol 1995; 39: 511_8.
12 Zhou HH, Anthony LB, Wood AJ, Wilkinson GR. Induction of
polymorphic 4'-hydroxylation of S-mephenytoin by rifampicin.
Br J Clin Pharmacol 1990; 30: 471_5.
13 Feng HJ, Huang SL, Wang W, Zhou HH. The induction effect of
rifampicin on activity of mephenytoin 4'-hydroxylase related to
M1 mutation of CYP2C19 and gene dose. Br J Clin Pharmacol
1998; 45: 27_9.
14 Yin OQP, Tomlinson B, Waye MMY, Chow AHL, Chow MSS.
Pharmacogenetics and herb_drug interactions: experience with
Ginkgo biloba and omeprazole. Pharmacogenetics 2004; 14:
841_50.
15 Wang LS, Zhou G, Zhu B, Wu J, Wang JG, Abd El-Aty AM,
et al. St John's wort induces both cytochrome P450 3A4-catalyzed
sulfoxidation and 2C19-dependent hydroxylation of omeprazole.
Clin Pharmacol Ther 2004; 75: 191_7.
16 Sun H, Zuo Z, Yin OQ, Tomlinson B, Chow MS. A
`high-throughput' cocktail method for screening the effect of herbal product
on liver isozyme activities: experience with Ginkgo
biloba. Clin Pharmacol Ther 2002; 45: 27_29.
17 Palovaara S, Tybring G, Laine K. The effect of ethinyloestradiol
and levonorgestrel on CYP2C19-mediated metabolism of
omeprazole in healthy female subjects. Br J Clin Pharmacol
2003; 56: 232_7.
18 Meng QH, Liu YS, Jing SM, Hu YZ. Study on the application of
index of composite information of chromatographic fingerprints
in quality control of traditional Chinese medicine. Chin J Nat
Med 2004; 2: 359_64.
19 Hao YN, Zhu XY, Cheng GF. Effects of baicalin on liver
microsomal cytochrome P450 system. Pharm J Clin PLA 2000;
16: 68_71.
20 Obach RS. Inhibition of human cytochrome P450 enzymes by
constituents of St John's wort, a herbal preparation used in the
treatment of depression. J Pharmacol Exp Ther 2000; 294: 88_95.
21 Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ,
Willson TM, et al. St John's wort induces hepatic drug
metabolism through activation of the pregnane X receptor. Proc Natl
Acad Sci USA 2000; 97: 7500_2.
22 Goodwin B, Hodgson E, Liddle C. The orphan human pregnane
X receptor mediates the transcriptional activation of CYP3A4
by rifampicin through a distal enhancer module. Mol Pharmacol
1999; 56: 1329_39.
23 Finch CK, Chrisman CR, Baciewicz AM, Self TH. Rifampin and
rifabutin drug interactions: an update. Arch Intern Med 2002;
162: 985_92.
24 Ferguson SS, Lecluyse EL, Megishi N, Goldstein JA. Regulation
of human CYP2C9 by the constitutive androstane receptor:
discovery of a new distal binding site. Mol Pharmacol 2002; 62:
737_46.
25 Lamba V, Lamba J, Yasuda K, Strom S, Davila J, Hancock ML,
et al. Hepatic CYP2B6 expression: gender and ethnic differences
and relationship to CYP2B6 genotype and CAR (constitutive
androstane receptor) expression. J Pharmacol Exp Ther 2003;
307: 906_22.
26 Lazar MA. East meets west: a herbal tea finds a receptor. J Clin
Invest 2004; 113: 23_5.
27 Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of
the cytochrome P4502C19 genetic polymorphism. Clin
Pharmacokinet 2002; 41: 913_58.
28 Plant NJ, Gibson GG. Evaluation of the toxicological relevance
of CYP3A4 induction. Curr Opin Drug Discov Devel 2003; 6:
50_6.
29 Sparreboom A, Cox MC, Acharya MR, Figg WD. Herbal
remedies in the United States: potential adverse interactions with
anticancer agents. J Clin Ontol 2004; 22: 12 2489_503.
|
