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Shaoyao-Gancao-Tang (SGT) is a traditional Chinese prescription containing Radix Paeoniae alba and Radix Glycyrrhizae and is commonly used to relieve pains. Albiflorin and paeoniflorin are the main effective compounds of Radix Paeoniae alba, and the pharmacokinetic differences of the two compounds in rats after oral administration of SGT and single herb Paeony decoction were studied. At different time points (5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, and 540 min) after administration, plasma concentrations of albiflorin and paeoniflorin were determined using a simple and reliable UPLC method, and main pharmacokinetic parameters were evaluated. It was found that there were significant differences (p

To investigate the effect of quercetin on organic anion transporting polypeptide 1B1 (OATP1B1) activities in vitro and on the pharmacokinetics of pravastatin, a typical substrate for OATP1B1 in healthy Chinese-Han male subjects.Using human embryonic kidney 293 (HEK293) cells stably expressing OATP1B1, we observed the effect of quercetin on OATP1B1-mediated uptake of estrone-3-sulphate (E3S) and pravastatin. The influence of quercetin on the pharmacokinetics of pravastatin was measured in 16 healthy Chinese-Han male volunteers receiving a single dose of pravastatin (40 mg orally) after co-administration of placebo or 500 mg quercetin capsules (once daily orally for 14 days).Quercetin competitively inhibited OATP1B1-mediated E3S uptake with a K(i) value of 17.9 ± 4.6 µm and also inhibited OATP1B1-mediated pravastatin uptake in a concentration dependent manner (IC(50) , 15.9 ± 1.4 µm). In healthy Chinese-Han male subjects, quercetin increased the pravastatin area under the plasma concentration - time curve (AUC(0,10 h) and the peak plasma drug concentration (C(max)) to 24% (95% CI 15, 32%, P0.001) and 31% (95% CI 20, 42%, P0.001), respectively. After administration of quercetin, the elimination half-life (t(1/2) ) of pravastatin was prolonged by 14% (95% CI 4, 24%, P = 0.027), with no change in the time to reach C(max) (t(max) ). Moreover, quercetin decreased the apparent clearance (CL/F) of pravastatin by 18% (95% CI 75, 89%, P0.001).These findings suggest that quercetin inhibits the OATP1B1-mediated transport of E3S and pravastatin in vitro and also has a modest inhibitory influence on the pharmacokinetics of pravastatin in healthy Chinese-Han male volunteers. The effects of quercetin on other OATP1B1 substrate drugs deserve further investigation.

Background Cytochrome P450 (CYP) oxidoreductase (POR) is the electron donor for microsomal CYP enzymes. The POR Ala503Val ( POR*28 C > T) polymorphism has been reported to influence CYP3A activity in vivo in a white population. The influence of this polymorphism on CYP3A activity in vivo in the Chinese population currently unknown. Objective This study was designed to assess the influence of the POR*28 polymorphism on the CYP3A activity in vivo in healthy Chinese men using midazolam (MID) as a probe drug. Methods The POR*28 polymorphism was genotyped in healthy Chinese men. A randomized, 2-phase, open-label, crossover study was performed to assess in vivo CYP3A activity after both oral and intravenous MID administration, which reflect both intestinal and hepatic CYP3A or only hepatic CYP3A activity, respectively. The plasma concentrations of MID and 1-hydroxy-midazolam (1-OH-MID) were determined by liquid chromatography–tandem mass spectrometry. Results A total of 73 healthy Chinese men were enrolled (CC genotype, 21 subjects; TT genotype, 11; CT genotype, 41), 22 of whom were selected for additional phenotyping of the CYP3A5*3 polymorphism (CC, 7; TT, 8; CT, 7). The mean (range) age, weight, height, and body mass index of the 22 subjects were 23 (20–28) years, 65.0 (57–75) kg, 1.74 (1.63–1.80) m, and 22.01 (19.27–24.46) kg/m 2 , respectively. The frequency of the POR*28 T (503V) allele was 43.2%. No significant differences in the demographic characteristics of the subjects were observed between the POR*28 genotype groups. All of the POR*28 CC and TT homozygotes and 2 of the POR*28 CT heterozygotes carried the CYP3A5*3/*3 genotype (CYP3A5 low expressors); 6 CT heterozygotes carried the CYP3A5*1 allele (CYP3A5 expressors). The mean (SD) 1-OH-MID AUC 0–8 was significantly greater in the TT homozygotes compared with the CT heterozygotes after intravenous (86.15 [24.34] vs 53.21 [31.36] ng/mL/h; P = 0.026) but not oral (126.36 [31.60] vs 103.09 [31.00] ng/mL/h; P = 0.159) MID administration. Mean 1-OH-MID C max was significantly greater in the TT homozygotes (51.40 [10.72] ng/mL) compared with the CC homozygotes (31.47 [11.54] ng/mL; P = 0.002) and CT heterozygotes (30.12 [9.21] ng/mL; P = 0.001) after intravenous MID administration. After intravenous MID injection, the MID metabolic ratio was significantly greater in the TT homozygotes compared with carriers of the C allele ( P = 0.031). Based on these findings, no significantly differences in overall (hepatic plus intestinal) CYP3A in vivo activity were observed between the POR*28 genotypes. Conclusion These findings suggest that individuals with the POR*28 C > T polymorphism underwent an increase in 1-hydroxylation of MID after intravenous MID administration, and that the polymorphism was associated with increased hepatic, but not intestinal, CYP3A activity in these healthy Chinese volunteers.

Mutations and/or deletions of Pkd1 in mouse models resulted in attenuation of osteoblast function and defective bone formation; however, the function of PKD1 in human osteoblast and bone remains uncertain. In the current study, we used lentivirus-mediated shRNA technology to stably knock down PKD1 in the human osteoblastic MG-63 cell line and to investigate the role of PKD1 on human osteoblast function and molecular mechanisms. We found that a 53% reduction of PKD1 by PKD1 shRNA in stable, transfected MG-63 cells resulted in increased cell proliferation and impaired osteoblastic differentiation as reflected by increased BrdU incorporation, decreased alkaline phosphatase activity, and calcium deposition and by decreased expression of RUNX2 and OSTERIX compared to control shRNA MG-63 cells. In addition, knockdown of PKD1 mRNA caused enhanced adipogenesis in stable PKD1 shRNA MG-63 cells as evidenced by elevated lipid accumulation and increased expression of adipocyte-related markers such as PPARγ and aP2. The stable PKD1 shRNA MG-63 cells exhibited lower basal intracellular calcium, which led to attenuated cytosolic calcium signaling in response to fluid flow shear stress, as well as increased intracellular cAMP messages in response to forskolin (10 µM) stimulation. Moreover, increased cell proliferation, inhibited osteoblastic differentiation, and osteogenic and adipogenic gene markers were significantly reversed in stable PKD1 shRNA MG-63 cells when treated with H89 (1 µM), an inhibitor of PKA. These findings suggest that downregulation of PKD1 in human MG-63 cells resulted in defective osteoblast function via intracellular calcium-cAMP/PKA signaling pathway.

To determine the effect of genistein on cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) function using the probe substrates midazolam and talinolol, respectively. Eighteen healthy adult male participants were enrolled in a two-phase randomized crossover design. In each phase, the participants received placebo or genistein for 14 days. On the 15th day, midazolam and talinolol were administered and blood samples were obtained. Midazolam and talinolol pharmacokinetic parameter values were calculated and compared before and after genistein administration. Co-administration of genistein decreased the area under the concentration-time curve from 0 to 36 h (AUC 0-36) (143.65 ± 55.40 ng h/mL versus 126.10 ± 40.14 ng h/mL, p 0.05), and the area under the concentration-time curve from zero to infinity (AUC 0-∞) (209.18 ± 56.61 ng h/mL versus 180.59 ± 43.03 ng h/mL, p 0.05), and also maximum concentration (Cmax) of midazolam (48.86 ± 20.21 ng/mL versus 36.25 ± 14.35 ng/mL p 0.05). Similarly, AUC 0-36 (2490.282 ± 668.79 ng h/mL versus 2114.46 ± 861.11 ng h/mL, p 0.05), AUC 0-∞ (2980.45 ± 921.09 ng h/mL versus 2626.92 ± 1003.78 ng h/mL, p 0.05) and Cmax of talinolol (326.58 ± 197.67 ng/mL versus 293.42 ± 127.19 ng/mL, p 0.05) were reduced by genistein co-administration. The oral clearance of midazolam (1.68 ± 0.85 h-1 versus 3.98 ± 0.59 h-1, p 0.05) and talinolol (3.34 ± 1.24 h-1 versus 3.79 ± 1.55 h-1, p0.05) were increased by genistien significantly. Administration of genistein can result in a modest induction of CYP3A and possibly P-gp activity in healthy volunteers.

1. The aim of this study was to investigate the association of the serine racemase (SRR) rs391300 G/A polymorphism with the risk of diabetes mellitus type 2 (T2DM) and to assess the impacts of the polymorphism on the therapeutic efficacy of metformin in Chinese patients. 2. A case-control study of 402 patients with T2DM and 171 healthy controls was conducted. The SRR rs391300 polymorphism was genotyped in all participants using the ABI 3700 automated sequencer. Forty-four recent-onset T2DM patients with different rs391300 genotypes were selected to receive 500 mg metformin orally daily for 12 consecutive weeks as monotherapy. Serum fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated haemoglobin (HbA1c), fasting serum insulin (FINS), postprandial serum insulin (PINS), triglycerol (TG), cholesterol (CHO), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), homeostasis model assessment for insulin resistance (HOMA-IR), and body mass index (BMI) were determined before and after metformin treatment. 3. The distribution frequencies of rs391300 were in agreement with Hardy-Weinberg equilibrium (P0.05). After treatment with metformin, the values of BMI, FPG, PPG, PINS, HbA1c, CHO, and TG decreased significantly (P0.01), whereas FINS increased (P0.001), in patients with T2DM. Patients with the GA or AA genotype of rs391300 showed better improvements in the levels of FPG, PPG, and CHO (P0.05) than individuals with the GG genotype. 4. The SRR rs391300 polymorphism was associated with the therapeutic efficacy of metformin in Chinese patients with T2DM.

Cisplatin toxicity severely obstacles successful chemotherapy in lung cancer patients. Cisplatin uptake is considered as one of the major factors contributing to the side effects of cisplatin. Genetic variances of core genes also affect cisplatin toxicity. It has been identified that CTR1, copper transporter protein 1, plays an essential role in cisplatin uptake. The purpose of this study is to investigate whether CTR1 polymorphism is associated with platinum toxicity in non-small cell lung cancer (NSCLC) patients.204 incident NSCLC patients from three different institutions were enrolled and followed up. These patients were histologically confirmed with non-small cell lung cancer. All patients have accepted cisplatin-based chemotherapy for at least two cycles. Twenty SNPs of CTR1 were detected in these patients.CTR1 rs10981694 AC polymorphism is associated with cisplatin induced severe toxicity in NSCLC patients. C-carrier subjects presented poorer tolerance to ototoxicity (p0.05). The survival times of patients with different rs10981694 genetic polymorphism were not significantly different.NSCLC patients carrying C allele of CTR1 rs10981694 presented more sensitivity to ototoxicity after cisplatin treatment. CTR1 plays an essential role in cisplatin toxicity and could be considered as a predictor for pretreatment evaluation in lung cancer patients.

Berberine is a plant alkaloid that is widely used to treat gastrointestinal infections, diabetes, hypertension, and hypercholesterolemia. Many studies have reported interactions between berberine-containing products and cytochromes P450 (CYPs), but little is known about whether berberine alters CYP activities in humans, especially after repeated doses.A two-phase randomized-crossover clinical study in healthy male subjects was performed. After 2 weeks of berberine (300 mg, t.i.d., p.o.) administration, midazolam, omeprazole, dextromethorphan, losartan, and caffeine were used to evaluate enzyme activities of CYP3A4, 2C19, 2D6, 2C9, and CYP1A2, respectively.A decrease in CYP2D6 activity was observed as the 0-8 h urinary dextromethorphan/dextrorphan increased ninefold (P 0.01). In addition, losartan/E-3174 ratio doubled (P 0.01) after BBR administration, indicating a decrease in CYP2C9 activity. CYP3A4 activity was also inhibited, as the C(max), AUC(0-∞), and AUC(0-12) of midazolam were increased 38% (P 0.05), 40% (P 0.01), and 37% (P 0.05) after BBR treatment, respectively. Compared with the placebo period, the T(max) and T(1/2) of midazolam during BBR administration were prolonged from 3.03 ± 0.27 to 3.66 ± 0.37 h and 0.66 ± 0.08 to 0.99 ± 0.09 h, respectively; the oral clearance of midazolam was decreased 27% (P 0.05); and the phenotypic indices of 1 h midazolam/1'-hydroxymidazolam increased 59% (P 0.01). There were no statistically significant differences in the pharmacokinetic parameters of the other probe drugs between placebo and the BBR-treated group.Repeated administration of berberine (300 mg, t.i.d., p.o.) decreased CYP2D6, 2C9, and CYP3A4 activities. Drug-drug interactions should be considered when berberine is administered.

1. In a previous in vitro study, we showed that the Arg723Gln (2168GA) polymorphism significantly ABCC1-induced multidrug resistance. The aim of the present study was to further investigate the association of this polymorphism with lung cancer susceptibility and chemotherapy response in a Chinese population. 2. A total of 77 lung cancer patients (54 men, 23 women) and 71 cancer-free controls (49 men, 22 women) were enrolled in the study. Genomic DNA was extracted from peripheral blood and all samples were genotyped using polymerase chain reaction-restriction fragment length polymorphism. 3. Individuals carrying the 723Gln (A) allele have a 3.4-fold increased risk (adjusted odds ratio (OR) 3.42; 95% confidence interval (CI) 1.29-9.06; P = 0.013) of lung cancer compared with wild-type individuals. Further stratified analysis indicated that older individuals (50 years) carrying the 723Gln (A) allele have the highest susceptibility to lung cancer (adjusted OR 4.10; 95% CI 1.25-13.48; P = 0.020). However, no substantial association was found between the Arg723Gln (2168GA) polymorphism and chemotherapy response in Chinese lung cancer patients. 4. In conclusion, the Arg723Gln (2168GA) polymorphism of ABCC1 appears to be a potential susceptibility marker for lung cancer in the Chinese population, especially in older people.

Objectives: To investigate the effects of magnesium lithospermate B (LAB) on intracellular reactive oxygen species (ROS) production induced by high dose of glucose or H 2 O 2 , we explored the influences of LAB on the expression of heme oxygenase-1 (HO-1) and nuclear factor E2-related factor-2 (Nrf2) in HEK293T cells after treatment with high dose of glucose. Materials and methods: The total nuclear proteins in HEK293T cells were extracted with Cytoplasmic Protein Extraction Kit. The ROS level was determined by flow cytometry. The mRNA and protein expression of HO-1 and Nrf2 were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. Results: LAB reduced the ROS production in HEK293T cells cultured under oxidative stress. High dose of glucose enhanced the expression of HO-1 mRNA and HO-1 protein in a time-dependent manner. LAB enhanced the expression of HO-1 mRNA and HO-1 protein in a dose-dependent manner treated with high dose of glucose. The amount of Nrf2 translocation was enhanced after cells were pretreated with 50 μmol/L or 100 μmol/L LAB. Silencing of Nrf2 gene eliminated the enhanced expression of HO-1 protein induced by high dose of glucose plus LAB. Conclusions: LAB plays an important role against glucose-induced intracellular oxidative damage. The enhanced expression of HO-1 mRNA and HO-1 protein caused by LAB is regulated via Nrf2 signal pathway.

1. In the present study, we investigated the associations of nicotinamide phosphoribosyltransferase (NAMPT)-3186 C/T and -948G/T polymorphisms with the risk of Type 2 diabetes mellitus (T2DM) and their impact on the efficacy of repaglinide in Chinese Han T2DM patients. 2. In all, 170 patients with T2DM and 129 healthy controls were genotyped for NAMPT-948GT and -3186CT polymorphisms. Thirty-five patients with different NAMPT -3186 C/T genotypes and the same organic anion-transporting polypeptide 1B1 (OATP1B1521) T/C genotype were randomly selected to undergo 8 weeks preprandial repaglinide treatment (1 mg, three times daily). Serum fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), glycated haemoglobin (HbAlc), fasting serum insulin (FINS), post-prandial serum insulin (PINS), triglyceride (TG), total cholesterol (CHO), homeostasis model assessment of insulin resistance (HOMA-IR), low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) were determined before and after repaglinide treatment. 3. After repaglinide treatment for 8 consecutive weeks, there were significantly decreases in PFG, PPG, HbAlc, CHO and LDL-C, and increases in FINS, HDL-C and the HDL-C : LDL-C ratio, in T2DM patients. The elevated PINS value in patients with CT genotypes was significantly lower than that in patients with the CC and TT genotypes (P0.05) and there were significant differences in CHO between patients with the CT genotype and the CC or TT genotype (P0.05). 4. The data suggest that the NAMPT -3186CT polymorphism is significantly associated with plasma levels of PINS and CHO in Chinese T2DM patients with repaglinide monotherapy.

Pharmacogenetics and pharmacogenomics are promising fields that will enable personalized therapy. However, one of the most important issues to be conquered in the practice of personalized medicine is the translation of scientific discoveries into better therapeutic outcomes. The international pharmacogenetic and pharmacogenomic approaches made in the field of personalized medicine and drug discovery are summarized in this review.

Uridinediphosphoglucuronate-glucuronosyltransferase (UGT) is the most important enzyme of the body in phase II metabolism. UGT is widely distributed in multiple tissues, including liver, kidney and intestine, which metabolizes a large number of exogenous toxic substances and endogenous substances. Studies found that UGT1 A genetic polymorphism is one of the important reasons for the variability of glucuronic acid metabolism between individuals. This paper reviews the current concept and new advances on UGT gene mutation.

Caffeine, a kind of alkaloid, extracted from tea and coffee fruit, is commonly used in the treatment of neurasthenia and for coma recovery. The metabolic process of caffeine in vivo is complex. Fifteen kinds of metabolites have been found, and the enzymes involved in the metabolic processes have also been confirmed. The urinary caffeine metabolites ratios are commonly used in the assessment of activities of drug metabolizing enzymes, mainly including CYP1A2, CYP2A6, N-acetyltransferase and xanthine oxidase. Methods for detection of caffeine and its metabolites have been improved steeply. In brief, caffeine has been paid close attention due to its intimate connection with human health as well as its importance in application in scientific research.

Selective serotonin reuptake inhibitors (SSRIs), one of popular antidepressants as "one-compound-one-target" paradigm, cannot but discontinue because of inhibiting gut movement. Traditional Chinese medicine (TCM) Chaihu-Sugan-San (CSS) can simultaneously exert anti-depression and prokinetics. From this thread, we aimed to find a new antidepressant with polypharmacological mechanisms. In vivo antidepressive and prokinetic comparisons between CSS and its absorbed compound ferulic acid (FA) were made. And FA's action mechanisms involved in monoaminergic systems, HPA axis and gastrointestinal peptide ghrelin was then studied in forced swimming test (FST) of rat. Lastly, the jejunal contraction activity evoked by FA was measured in vitro. Compared with vehicle, FA reduced immobility time, increased locomotor activity, accelerated gastric emptying and intestinal transit similar to CSS whose absorbable component FA was identified in hippocampus and jejunum. FA's prokinetics in vivo was further supported by its jejunal contraction in vitro. FA-induced anti-immobility was prevented by pretreated with PCPA, WAY-100635, ketanserin, sulpiride, SCH233390, haloperidol and yohimbine, respectively. CRH, ACTH and 5-HT were significantly decreased, but ghrelin was apparently increased compared with vehicle. In summary, FA induced anti-depression and prokinetics similar to CSS via inhibiting serotonin, norepinephrine and dopamine reuptakes, regulating HPA axis, increasing ghrelin and stimulating jejunal contraction simultaneously.

Aims We aimed to detect optimal ratio of cardioprotection-dependent absorbed bioactive compounds (ABCs) as quality control of Guan-Xin-Er-Hao (GXEH) formula extracted by various processings. Methods Ferulic acid (F), tanshinol (T), hydroxysafflor yellow A (A), protocatechualdehyde (P) and paeoniflorin (E) in GXEH formula and FTA in blood from rat with acute myocardial infarction (AMI) were first identified by HPLC–MS/MS, and FTAPE in GXEH formulae with various herbs, extraction times and extraction water volumes were then quantitated only by HPLC. Results FTAPE in various GXEH were determined. FTA were selected as GXEH's ABCs. Ratios of FTA were determined, suggesting the high (1:6.1:15.6), medium (1:1.7:15.2) and low (1:0.2:15.3) ratios. Three FTA ratios and their parent formulae ratio-dependently reduced infarct size, myocardial apoptosis and caspase-3 activity. Conclusion There is the optimal ratio of F:T:A among various formulae, contributing to the best cardioprotection. This FTA ratio was developed as quality control of GXEH formula.

This experiment studied the potential effect of meranzin hydrate (MH) and decoction of herb Fructus Aurantii (FA) on rat gut motility. It also investigated the prokinetic mechanism of MH. Experiments were performed on male Sprague–Dawley rats (200–220 g). The study included: (1) qualitation of MH and four other known compounds in FA and jejunum after oral administration of FA decoction to rats; (2) in vitro experiment of MH on rat jejunum contractions; (3) in vivo experiment of FA and MH in rats. Dose-dependently, MH (1–100 µM) increased amplitude in longitudinal and circular jejunum muscles. Pretreatment of jejunum longitudinal strips with benzhydramine (1 µM) remarkably inhibited the contractions induced by histamine (1 µM) and MH (10 or 30 µM). Pretreatment of jejunum longitudinal strips with atropine (1 µM) reduced the contractions induced by acetylcholine (1 µM) but did not influence the contractions induced by MH (10 or 30 µM). Interestingly, the antagonism of benzhydramine to MH was also verified in vivo. MH can be absorbed into the jejunum following oral administration of FA decoction. In healthy rats, MH (7, 14, and 28 mg/kg) and FA (3.3, 10, and 20 g/kg) both promoted intestinal transit and gastric emptying in a dose-dependent manner when gavaged acutely. In cisplatin model rats, MH (14 and 28 mg/kg) significantly reversed cisplatin-induced delay in gastric emptying. Meranzin hydrate can induce similar effect to Fructus Aurantii on intestinal motility and it was, at least in part, mediated by stimulation of H1 histamine receptors.

To investigate whether the insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) rs1470579 and rs4402960 polymorphisms are associated with the development of type 2 diabetes mellitus (T2DM) and the repaglinide therapeutic efficacy in Chinese T2DM patients. A case-control study of a total of 350 patients with T2DM and 207 healthy volunteers was conducted to identify their genotypes for the IGF2BP2 rs1470579 and rs4402960 polymorphisms using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Forty-two patients were randomly selected to undergo an 8-week repaglinide treatment (3 mg/d). Fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin (HbAlc), fasting serum insulin (FINS), postprandial serum insulin (PINS), homeostasis model assessment for insulin resistance (HOMA-IR), serum triglyceride, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), and high-density lipoprotein-cholesterol (HDL-c) were determined before and after repaglinide treatment. The frequencies of the IGF2BP2 rs1470579 C allele and the rs4402960 T allele were higher in T2DM patients than in healthy controls (P

Curcumin is a kind of plant polyphenol that is extracted from the rhizome of Curcuma longa. Studies about the effect of curcumin on the activity of drug-metabolizing enzymes in humans are lacking.To investigate the effect of curcumin on the activities of CYP1A2, CYP2A6, N-acetyltransferase (NAT2), and xanthine oxidase (XO) in vivo, using caffeine as a probe drug.Sixteen unrelated, healthy Chinese men were recruited for the study. There were 2 phases in the study. In the first phase, volunteers orally received 100 mg caffeine and 0- to 12-hour blood and urine samples were collected. In the second phase, volunteers received 1000 mg curcumin once daily for 14 continuous days, and blood and urine samples were collected on day 15, following the same procedure used on the first day. Urinary caffeine metabolite ratios were used as the indicators of the activities of CYP1A2, CYP2A6, NAT2, and XO. The pharmacokinetics of caffeine and its metabolites were determined by high-performance liquid chromatography.In the curcumin-treated group, CYP1A2 activity was decreased by 28.6% (95% CI 15.6 to 41.8; p0.000), while increases were observed in CYP2A6 (by 48.9%; 95% CI 25.3 to 72.4; p0.000). Plasma area under the curve from zero to 12 hours of 1,7-dimethylxanthine (17X) was decreased by 27.2% (95% CI 6.1 to 48.3; p = 0.014). The urinary excretion of 17X and 1-methylxanthine was significantly decreased by 36.4% (95% CI 19.4 to 53.6; p0.000) and 31.2% (95% CI 8.5 to 54.1; p = 0.010), respectively. The excretion of 1,7-dimethylurate (17U) was significantly increased by 77.3% (95% CI 5.6 to 148.8; p = 0.036). No significant changes were observed for caffeine, 1-methylurate, and 5-acetylamino-6-formylamino-3-methyluracil between the 2 study phases.The results indicated that curcumin inhibits CYP1A2 function but enhances CYP2A6 activity. Simultaneously, some pharmacokinetic parameters relating to 17X were affected by curcumin. If this finding is confirmed by other studies, the possibility of herb-drug interactions associated with curcumin should be considered in clinical practice.

Objective To establish the theories and methods to determine apparent solubility paraneters of multiple components for the Chinese materia medica (CMM) with HPLC fingerprint. Method The mathematical functional expresses to determine the apparent solubility parameters for multiple constituents were established according to total quantum geometrical average retention time (TQGART) for HPLC fingerprint that characterized the entirety tendencies for all-over chromatographic peaks, validated by the aloe-emodin's solubility parameters which had been determined. The HPLC for the aloe-emodin's solubility parameters were carried out with an Alltech Apollo C18 as column, Acetone: Water as mobile phase, gradient elution,flow rate as 1.0 mL x min(-1), the detection wave-length as 430 nm and the temperature as 30 degrees C. Result The mathematical functional model between the TQGART of HPLC chromatographic fingerprint and the total quantum apparent solubility parameters was established and used to determine the aloe-emodin's mixture solubility parameter as 36.12 J(1/2) x cm(-3/2), nearly equal to 35.57, 36.07 J(1/2) x cm(-3/2) calculated by ration of peak area ratios and molecular fraction, respectively. Conclusion The TQGART of HPLC fingerprint can be used to determine simultaneously the apparent or single intrinsic solubility parameters for total quantum or intrinsic solubility parameters for single in multiple constitute systems, by which theoretical and technologic platform to study the compatibility rule and dosage form reform of the single CMM will be established.

Ilaprazole is a new proton pump inhibitor designed for the treatment of gastric ulcers, and limited data is available on the metabolism of the drug. In this article, the structural elucidation of urinary metabolites of ilaprazole in human was described by HPLC-ESI-MS/MS and stopped-flow HPLC-NMR experiments. Urinary samples were precipitated by sodium carbonate solution, and then extracted by liquid–liquid extraction after adding ammonium acetate buffer solution. The enriched sample was separated using a C18 reversed-phase column with the mobile phase composed of acetonitrile and 0.05 mol/L ammonium acetate buffer solution in a gradient solution, and then directly coupled to ESI-MS/MS detection in an on-line mode or 1H-NMR (500 MHz) spectroscopic detection in a stopped-flow mode. As a result, four sulfide metabolites, ilaprazole sulfide (M1), 12-hydroxy-ilaprazole sulfide (M2), 11,12-dihydroxy-ilaprazole sulfide (M3) and ilaprazole sulfide A (M4), were identified by comparing their MS/MS and NMR data with those of the parent drug and available standard compounds. The main biotransformation reactions of ilaprazole were reduction and the aromatic hydroxylation of the parent drug and its relative metabolites. The result testified that HPLC-ESI-MS/MS and HPLC-NMR could be widely applied in detection and identification of novel metabolites. Copyright © 2010 John Wiley & Sons, Ltd.

Guanxin II (GXII) is a traditional Chinese formula to treat coronary heart disease in China. Previous studies indicate cardioprotection of GXII are related to cardiomyocyte apoptosis. Akt is necessary and sufficient for inhibition of apoptosis in cardiomyocytes. Our aim was to examine whether or not the antiapoptotic mechanisms of GXII are related to the Akt pathway. Male Sprague-Dawley rats were randomly assigned to four groups: GXII administered at 2.5 or 0.5 g raw materials/kg, the vehicle control and sham-operated oral 0.9% NaCl. They were pretreated once a day for 15 consecutive days by gavage. Thirty min after the last administration, the left anterior descending coronary artery was occluded to induce myocardial ischemia except for the sham-operated rats. Compared with rats receiving vehicle, those rats pretreated with GXII at 2.5 g/kg significantly reduced infarct size and decrease apoptosis. Furthermore, GXII (2.5 g/kg) significantly activated Akt kinase, increased the Bcl-2/Bax ratio, inhibited cytochrome c release, reduced caspase-9 activation, and attenuated subsequent caspase-3 activation. GXII at 0.5 g/kg have no noticeable effect on these parameters. Meanwhile, GXII at 2.5 g/kg did not change myocardial blood flow of ischemic zone, indicating a direct action on cardiomyocytes. These results suggest GXII at 2.5 g/kg ensures the survival of myocardium by enhancing the Akt-mediated antiapoptosis pathway. The findings provide new evidence of the effective and safe therapy with GXII for patients with chronic coronary heart disease.

The current study is to determine the alterations of efflux transport activity to Rh123 and sensitivity to anticancer agents mediated by a MDR1 C2005T polymorphism. Expressions of mRNA and protein of MDR1 were measured by real-time PCR and immunoblotting, respectively, and localization of P-glycoprotein (P-gp) by confocal microscopy. Cell cytotoxicity and efflux transport activity were determined by MTT and Rh123 transepithelial permeability assay, respectively. MDR1 C2005T polymorphism did not affect the expression level of the MDR1 mRNA and protein and had no effect on the trafficking of P-gp to plasma membrane. A cytotoxicity study showed that MDR1wt and MDR1 2005T cells exhibited similar resistance, as measured by IC50 values, to vinblastine (30.3 ± 2.5 vs. 32.5 ± 1.7 nM) and vincristine (104.1 ± 1.9 vs. 110.3 ± 3.5 nM). However, MDR1 2005T cells were less resistant to paclitaxel (28.2 ± 2.1 vs. 91.8 ± 3.5 nM; P

To determine if differences exist between Chinese and white subjects in their response to atropine and if the intrinsic heart rate and the autonomic contribution to the heart differ between the two races, eight white and eight Chinese males were studied. In all subjects the heart rate decreased after the first dose of atropine (0.003 mg/kg) with no difference in the bradycardia between the two races. However, as further doses were administered, the heart rate increased in both groups, resulting in a significantly (p < 0.05) greater increase in Chinese subjects than in white subjects. The increase in heart rate for each nanogram per milliliter of atropine was 2.8-fold higher (p < 0.05) in the Chinese subjects (19.24 ± 4.41 beats/min) compared with white subjects (6.83 ± 1.62 beats/min). There was no difference in the intrinsic heart rate, in the relative vagal contribution, or in relative sympathetic contribution to the heart rate between the Chinese and white subjects. These data indicate that Chinese subjects are more sensitive to the effect of atropine, which is not related to the contribution of autonomic tone to the heart. Clinical Pharmacology and Therapeutics (1992) 52, 120–124; doi:10.1038/clpt.1992.120

Ge-gen (Radix Puerariae) is used in traditional oriental medicine for various medicinal purposes. The drug is the root of a wild leguminous creeper, Pueraria lobata (Willd) Ohwi. It possesses a high content of avonoid derivatives, the most abundant of which is puerarin. Our goal was to find the effect of puerarin on cytochrome P450 enzymes in vivo. The study was conducted in 18 male volunteers of different genotypes (CYP2D6 *1/*1, *1/*10, *10/*10). Plasma was obtained at 6 h after oral administration and urine was collected from 0 to 8 h after probe drug administration. The logarithm value of metabolic rate decrease from -0.0055 +/- 0.1887 to -0.1754 +/- 0.2411 implied puerarin inhibited activity of CYP2D6. There was no significant relationship between the inhibition with the CYP2D6 genotypes. The paraxanthin/caffeine ratio in the plasma sample at 6th hour was increased by 30 +/- 47% (p = 0.003), implied puerarin induced the activity of CYP1A2. While puerarin used together with the substrates of both enzymes, drug interaction worth the attention and at sometimes precautions are needed.

Background Losartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E-3174, which has greater antihypertensive activity than the parent compound. Soy extract has been shown to be an activator of CYP2C9 and CYP3A4 in vitro. Coadministration of soy extract and losartan may therefore after the pharmacokinetics of losartan and E-3174. Objective To determine whether, when losartan was used in combination with soy extract, a significant pharmacokinetic interaction would be observed in healthy female volunteers. Methods Eighteen healthy Chinese female volunteers were recruited. In an open-label, 2-phase study, losartan 50 mg was given to each subject, with and without soy extract. Plasma concentrations of losartan and E-3174 were determined by liquid chromatography–tandem mass spectrometry for 12 and 24 hours, respectively. On day 8 through day 21 of the study, following a 7-day washout period, each subject consumed two 1000-mg Genistein Soy Complex tablets orally after meals, twice daily, for 14 days. On day 22, all volunteers received losartan 50 mg and blood samples were collected again. Results All subjects completed the study, without adverse drug effects. Over the 14-day pretreatment period, soy extract did not significantly influence the pharmacokinetics of losartan or E-3174. The ratio of the area under the curve of the drug and metabolite after losartan administration, with and without soy extract ingestion, was 0.21 ± 0.05 and 0.23 ± 0.05 (mean ± SD), respectively. The difference was not statistically significant (p = 0.22). Conclusions Our data indicate that a significant interaction between soy extract and losartan is unlikely to occur in females.

Background Ginkgo biloba extract (GBE), the best selling herbal medicine in the world, has been reported to inhibit P-glycoprotein in vitro. However, the effects of GBE on P-glycoprotein activity in humans have not been clarified. Objective To investigate the effects of single and repeated GBE ingestion on the oral pharmacokinetics of talinolol, a substrate drug for P-glycoprotein in humans. Methods Ten unrelated healthy male volunteers were selected to participate in a 3-stage sequential study. Plasma concentrations of talinolol from 0 to 24 hours were measured by high-performance liquid chromatography after talinolol 100 mg was administrated alone, with a single oral dose of GBE (120 mg), and after 14 days of repeated GBE ingestion (360 mg/day). Results A single oral dose of GBE did not affect the pharmacokinetics of talinolol. Repeated ingestion of GBE increased the talinolol maximum plasma concentration (Cmax) by 36% (90% CI 10 to 68; p = 0.025), the area under the concentration-time curve (AUC)0-24 by 26% (90% CI 11 to 43; p = 0.008) and AUC0-∞ by 22% (90% CI 8 to 37; p = 0.014), respectively, without significant changes in elimination half-life and the time to Cmax. Conclusions Our results suggest that long-term use of GBE significantly influenced talinolol disposition in humans, likely by affecting the activity of P-glycoprotein and/or other drug transporters.

This study explores the impact of clopidogrel on the pharmacokinetics of omeprazole related to CYP2C19 genetic polymorphisms. Twelve healthy volunteers (6 CYP2C19*1/*1, 5 CYP2C19*2/*2, and 1 CYP2C19*2/*3) are enrolled in a 2-phase randomized crossover trial. In each phase, the volunteers are administered a single oral dose of omeprazole 40 mg after pretreatment of either placebo or clopidogrel (300 mg on the first day and then 75 mg once daily for 3 consecutive days). Plasma concentrations of omeprazole and its metabolites are quantified by high-performance liquid chromatography with UV detection. After clopidogrel treatment, the AUC(0-infinity) of omeprazole increases by 30.02% +/- 18.03% (P = .004) and that of 5-hydroxyomeprazole decreases by 24.30% +/- 11.66% (P = .032) in CYP2C19*1/*1. The AUC(0-infinity) ratios of omeprazole to 5-hydroxyomeprazole increase by 74.98% +/- 35.48% (P = .001) and those of omeprazole to omeprazole sulfone do not change significantly (P = .832) in CYP2C19*1/*1. No significant alteration is observed in CYP2C19*2/*2 or *3. Clopidogrel inhibits CYP2C19-dependent hydroxylation of omeprazole in CYP2C19*1/*1 and has no impact on CYP3A4-catalyzed sulfoxidation of omeprazole.

Aim To evaluate the potential drug-drug interactions between bifendate and cyclosporine, a substrate of CYP3A4, in relation to different CYP3A4*18B genotype groups. Methods Eighteen unrelated healthy subjects (six CYP3A4*1*1, six CYP3A4*1/*18B, and six CYP3A4*18/*18B) were selected for this study. After repeated oral administration of a placebo or bifendate (three times daily for 14 d), the whole-blood level of cyclosporine was measured using high performance liquid chromatography-electrospray mass spectrometry (HPLC/ESI-MS). This study was carried out in a two-phase randomized crossover manner. Results After the treatment with bifendate, the areas under the curve (AUC(0-24) and AUC(0-infinity)) decreased significantly by 9.7%+/-3.7% (P=0.01) and 19.2%+/-16.8% (P=0.001) in CYP3A4*1/*1 subjects, 11.3%+/-9.4% (P=0.03) and 10.5%+/-9.6% (P=0.043) in CYP3A4*1/*18B subjects, and 40.2%+/-14.7% (P=0.02) and 37.5%+/-15.8% (P=0.003) in CYP3A4*18B/*18B subjects. Meanwhile, the decreases in the AUC(0-24) and AUC(0-infinity) values in the three groups were significantly different (using one-way analysis of variance, P=0.001 and P=0.001), and the change in the CYP3A4*18B/*18B group was greater than that in the other two groups. The oral clearance of cyclosporine was altered in all the subjects, with substantial increases by 10.2%+/-4.4% (P=0.004) in CYP3A4*1/*1 subjects, 14.0%+/-12.0% (P=0.048) in CYP3A4*1/*18B subjects, and 32.4%+/-21.7% (P=0.013) in CYP3A4*18B/*18B subjects. Conclusion These results suggest that bifendate decreases the plasma concentration of cyclosporine in a CYP3A4 genotype-dependent manner.

To explore the distribution frequencies of four common single nucleotide polymorphisms (SNPs) of MRP1/ABCC1 in a mainland Chinese population and investigate whether these SNPs affect the expression and function of the MRP1/ABCC1.The genotype of 208 healthy volunteers was determined using PCR-restriction fragment length polymorphism. The four candidated SNPs were recreated by site-directed mutagenesis and tested for their effect on MRP1/ABCC1 expression and multidrug resistance function in stable transfected HEK293 and CHO-K1 cell lines. Real-time PCR, western blot and confocal microscopy were used to determine the mRNA, protein expression, and protein trafficking. At last, the effect of mutations on MRP1/ABCC1-mediate drug resistance was determined using methyl thiazolyl tetrazolium assay.The allelic frequencies of Cys43Ser (128GC), Thr73Ile (218CT), Arg723Gln (2168GA), and Arg1058Gln (3173GA) in mainland Chinese were 0.5, 1.4, 5.8, and 0.5%, respectively. None of these mutations had any effect on MRP1/ABCC1 expression and trafficking, but that Arg723Gln mutation significantly reduced MRP1/ABCC1-mediated resistance to daunorubicin, doxorubicin, etoposide, vinblastine, and vincristine. The Cys43Ser mutation did not affect all tested drug resistance. In contrast, the Thr73Ile mutation reduced resistance to methotrexate and etoposide, whereas the Arg1058Gln mutation increased the response of two anthracycline drugs and etoposide in HEK293 and CHO-K1 cells as well as vinblastine and methotrexate in CHO-K1 cells.The allelic frequency of the Arg723Gln mutation is relatively higher than other SNPs in mainland Chinese population and therefore this mutation significantly reduces MRP1/ABCC1 activity in multidrug resistance.

1. Quercetin, one of the most abundant natural flavonoids, has been reported to modulate the activity of several drug-metabolising enzymes. The aim of the present study was to investigate the effects of quercetin on cytochrome P450 (CYP) 1A2, CYP2A6, N-acetyltransferase (NAT2) and xanthine oxidase (XO) activity in healthy volunteers using caffeine as a probe drug. 2. Twelve unrelated, healthy volunteers were recruited to the study. There were two phases to the study; in the first phase, each subject was given a single oral dose of caffeine (one 100 mg capsule) with 150 mL water; in the second phase, each subject was give a 500 mg quercetin capsule once daily for 13 continuous days and was coadministered a 100 mg caffeine capsule on the 13th day. Urinary caffeine metabolite ratios were used as indicators of the activity of CYP1A2, CYP2A6, NAT2 and XO. The pharmacokinetics of caffeine and its metabolites were determined by HPLC. 3. In the quercetin-treated group, CYP1A2 activity was decreased by 10.4% (95% confidence interval (CI), 1.1-29.8%; P = 0.039), whereas increases were observed in CYP2A6 (by 25.3%; 95% CI, 6.2-34.5%; P = 0.002), NAT2 (by 88.7%; 95% CI, 7.1-160.2%; P = 0.010) and XO activity (by 15.0%; 95% CI, 1.6-21.6%; P = 0.007). Plasma C(max) and the AUC((0-24 h)) of 1,7-dimethylxanthine were decreased by 17.2% (95% CI, 6.4-28.0%; P = 0.024) and 16.2% (95% CI, 3.9-28.5%; P = 0.032), respectively. The urinary excretion of 1,7-dimethylxanthine and 1-methylxanthine was significantly decreased by 32.4% (95% CI, 2.5-62.1%; P = 0.036) and 156.1% (95% CI, 53.3-258.9%; P = 0.004), respectively. The urinary excretion of 1,7-dimethylurate and 1-methylurate was increased by 82.9% (95% CI, 56.0-165.4%; P = 0.030) and 97.8% (95% CI, 12.1-183.5%; P = 0.029), respectively. No changes were observed in the urinary excretion of caffeine and 5-acetylamino-6-formylamino-3-methyluracil between the two study phases. 4. The results of the present study indicate that quercetin inhibits CYP1A2 function, but enhances CYP2A6, NAT2 and XO activity. Simultaneously, some pharmacokinetic parameters relating to 1,7-dimethylxanthine were affected by quercetin. Thus, we conclude that quercetin affects CYP1A2, CYP2A6, NAT2 and XO activity in vivo.

Sensitivity to the hypotensive effect of propranolol differs between Chinese subjects and white subjects. To explore the pharmacodynamic explanation for this difference, eight Chinese subjects (age range, 25 to 42 years) and eight white subjects (age range, 22 to 36 years) were given single doses of 10, 20, 40, and 80 mg propranolol on separate occasions at least 3 days apart. Heart rate, mean blood pressure, norepinephrine, epinephrine, and plasma renin activity were measured at the end of treadmill exercise 2 hours after medication was administered. Propranolol produced a concentration-dependent reduction in mean blood pressure and heart rate in both groups. Concentration-response curves were shifted significantly to the left in Chinese subjects, confirming the increased sensitivity to propranolol of the Chinese. The baseline exercise plasma renin activity was twofold higher (p < 0.05) in Chinese than in white subjects. The sensitivity to β-blockade—induced suppression of plasma renin activity was increased in the Chinese, which resulted in a sevenfold higher concentration being required in white subjects than in Chinese to produce the same 50% suppression of exercise plasma renin activity (84.8 ± 23.2 versus 12.7 ± 7.4 ng/ml, p < 0.05). The reduction in exercise heart rate and mean blood pressure produced by propranolol were well correlated to the reduction in exercise plasma renin activity in both populations. There was no significant effect of either race or propranolol on plasma catecholamine concentration after exercise. The findings indicate that the previously demonstrated higher sensitivity to β-blockade produced by propranolol also extends to the β -receptor—mediated effect on renin activity and this increased sensitivity to plasma renin activity suppression in Chinese subjects may partially explain their increased sensitivity to the hypotensive effects of propranolol. Clinical Pharmacology and Therapeutics (1991) 50, 150–156; doi:10.1038/clpt.1991.119

This study investigated the effect of the herbal medicine baicalin on bupropion hydroxylation, a probe reaction for CYP2B6 activity related to different CYP2B6 genotype groups. Seventeen healthy male volunteers (6 CYP2B6*1/*1, 6 CYP2B6*1/*6, and 5 CYP2B6*6/*6) received orally administered bupropion alone and during daily treatment with baicalin. Blood samples were taken up to 72 h after each bupropion dose, and pharmacokinetics profiles were determined on days 1 and 25 for bupropion and hydroxybupropion. Baicalin administration increased hydroxybupropion maximum plasma concentration (C max) by 73% [90% confidence interval (CI), 44–108%; P

In the current study, we investigated the effects of genistein on adipogenic differentiation of mouse bone marrow-derived mesenchymal stem cell (BMSC) cultures and its potential signaling pathway. The terminal adipogenic differentiation was assessed by western-blotting analysis of adipogenic-specific proteins such as PPARgamma, C/EBPalpha, and aP2 and the formation of adipocytes. Treatment of mouse BMSC cultures with adipogenic cocktail resulted in sustained activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are members of the mitogen-activated protein kinase (MAPK) family, at the early phase of adipogenesis (from days 3 to 9). Inhibition of ERK1/2 activation by PD98059, a specific MEK inhibitor, reversed the induced adipogenic differentiation. Genistein dose-dependently decreased the phosphorylation of ERK1/2 in mouse BMSC cultures. Genistein incubation for the entire culture period, as well as that applied during the early phase of the culture period, significantly inhibited the adipogenic differentiation of mouse BMSC cultures. While genistein was incubated at the late stage (after day 9), no inhibitory effect on adipogenic differentiation was observed. BMSC cultures treated with genistein in the presence of fibroblast growth factor-2 (FGF-2), an activator of the ERK1/2 signaling pathway, expressed normal levels of ERK1/2 activity, and, in so doing, are capable of undergoing adipogenesis. Our results suggest that activation of the ERK1/2 signaling pathway during the early phase of adipogenesis (from days 3 to 9) is essential to adipogenic differentiation of BMSC cultures, and that genistein inhibits the adipogenic differentiation through a potential downregulation of ERK1/2 activity at this early phase of adipogenesis.

Heterogeneous nuclear ribonucleoprotein ( hnRNPs) is a widely expressing protein family in human body,which has a close relationship with health. HnRNPs takes part in the developing processes of many diseases such as viral diseases, tumor, autoimmune system diseases and so on. hnRNPs also regulates the expression of special genes such as cyp2a5, CYP2A6, eNOS. There are numerous proteins in vivo and hnRNPs links with them in numerous ways. Much work is needed to unclose the relationship between hnRNPs and related diseases or gene regulation.

To study the pharmacokinetic characteristics of voriconazole in healthy Chinese male volunteers in relation to cytochrome P450 (CYP) 2C19 genotype status, including ultra-rapid metabolizers (URMs), homozygous extensive metabolizers (EMs), and poor metabolizers (PMs).Twenty healthy Chinese male volunteers were recruited for the study. Of these, four were CYP2C19 heterozygous URMs (*1/*17), eight were CYP2C19 homozygous EMs (*1/*1), and eight were CYP2C19 PMs (*2/*2). After a single oral dose of 200 mg voriconazole, plasma concentrations of voriconazole were determined for a 24-h period by liquid chromatography-mass spectrometry/mass spectrometry.In Chinese male subjects, the allele frequencies of the CYP2C19*17 and CYP2C19*2 alleles were 0.64 and 35.6%, respectively, and both alleles were in Hardy-Weinberg equilibrium. The area under the concentration-time curve (AUC) from predose to 24 h (AUC(0-24)) and from predose to infinity (AUC(0-infinity)), and apparent oral clearance (CL/F) of voriconazole were statistically different among all three genotypic groups (P0.001, respectively). The maximum plasma concentration (C(max)) value of URMs also showed statistically significant differences from those of EMs and PMs (P = 0.036 and P = 0.035, respectively). The elimination half-life (t(1/2)) in URMs was 87% (P = 0.58) of that in EMs and 51% (P= 0.002) of that in PMs.Our data indicate that the presence of the CYP2C19*17 allele results in ultra-rapid metabolism of voriconazole after a single oral dose.

To establish the theories and methods to determine solubility parameters of multiple components for the traditional Chinese material medica (TCMM) with HPLC.The mathematical expresses to determin the solubility parameters were established according to chromatographic and Hildebrand-Scatchard theories, The HPLC experiments were carried out at 40 degrees C on an Alltech Apollo C18 column (4.6 mm x 250 mm, 5 microm) eluted with acetone and water in gradient mode. The flow rate was 1.0 mL min(-1), and the detection wavelength was 254 nm. The injection volume was 1 0 microL.The mathematical expresses between the retention time and the solubility parameters were established and used to determin caffeine solubility parameter as 28.31 J(1/2) cm(-3/2) in accordance with 28.84 J(1/2) cm(-3/2) reported by literature, and those of aloe-emodin, rhein, emodin, physcione as 39.70 J(1/2) cm(-3/2), 39.08 J(1/2) cm(-3/2), 38.37 J(1/2) cm(-3/2), 36.42 J(1/2) cm(-3/2) respectively.The retention time of HPLC can be used to determine the solubility parameters of multiple componets. The established method is useful for the compatibility rule study of traditional Chinese medicine.

To explore the frequency of vitamin D receptor (VDR) Fok I polymorphism in healthy Chinese and colorectal tumor patients,and to study the correlation between VDR Fok I polymorphism and the pathogenesis of colorectal tumor.After the preparation of gDNA by common method,VDR genotypes were determined by Fok I restriction endonuclease digestion of PCR-amplified DNA in 69 colorectal cancer patients and 218 healthy persons.The F allele frequencies of VDR in healthy persons and in colorectal tumors patients were 61.5% and 49.3%, respectively, with statistical difference (P0.05). The genotype frequencies of FF, Ff and ff in healthy persons and in colorectal tumors patient were (39.5%,44%,16.5%) and (29.1%,40.5%,30.4%), respectively,with statistical differences (P0.05). The odds ratio of ff and Ff genotypes were 2.51 (95% confidence interval,1.21 approximately 5.18) and 2.00 (95% confidence intervals,1.01approximately 3.96), respectively (P0.01).Fok I polymorphism is a common single nucleotide polymorphism (SNP) of VDR in Chinese population,and the VDR Fok I polymorphism may lower the risk of colorectal tumor.

CYP1A2 is an important cytochrome P450 enzymes, which is involved in metabolism of many clinical drugs and activation of some precarcinogens. CYP1A2 activity can be influenced by various factors including genetic polymorphism, drugs, food and so on, in which the CYP1A2 genetic polymorphism is the basis of difference on the activity and induction of CYP1A2. Therefore,the genotyping of CYP1A2 plays an important part in individualization of therapy.

Ligularia is mainly distributed in the western regions of China. Most of the species have been traditionally used in folk medicine for the treatment of hepatitis B, asthma, hemoptysis and pulmonary tuberculosis. In our continuation of research on antiviral components from traditional Chinese medicine, Ligularia atroviolacea was tested for inhibitory effects on hepatitis B virus (HBV). A bioassay-guided phytochemical examination of L. atroviolacea disclosed that its ethyl acetate extract, which was made up of two eremophilenolides, showed suppressive activity on the expression of HBV surface antigen (HBsAg) in the HepG2.2.15 cell line. Then a simple and effective preparative high-speed counter-current chromatography method was successfully developed for the isolation and purification of two main active metabolites, 8beta-hydroxyeremophil-3,7(11)-dien-12,8alpha;15,6alpha-diolide and 8beta-methoxyeremophil-3,7(11)-dien-12,8alpha;15,6alpha-diolide from the ethyl acetate extract of L. atroviolacea by a one-step separation using a two-phase solvent system composed of light petroleum (60-90 degrees C)-ethyl acetate-methanol-water (9:1:8:2, v/v/v). The chemical structures of the two eremophilenolides were identified by ESI-MS, (1)H-NMR and (13)C-NMR analysis. The anti-HBV activity of the two purified compounds was measured; both of them showed suppressive activity on the expression of HBsAg in the HepG2.2.15 cell line. The results support the continued and expanded exploitation and utilization of L. atroviolacea.

A new qualitative and quantitative analytical method of the chromatographic fingerprints: the Total Quantum Statistical Moment (TQSM) has been eluciated and established according to statistical moment principle. The study was carried out with model drugs as the alcohol extracted liquid for Radix et Rhizoma Rhei (AELRR) by HPLC under the chromatographic conditions that the column was C18, 4.6 mm x 250 mm, 5 microm; the detection of wavelengths was set at 254 nm; a solution of acetonitrile: 1% acetic acid water (from 0:100 to 100:0) was carried with gradient elution as the mobile phase; the ratio of flow was 1 mL min(-1); the temperature was 40 degrees C. The coefficients were dealt with Excel document. It has been established the expressions that consists of four main parameters: 1) total quantum zero moment as AUC(T), area under curve; 2) total quantum respondent ratio as AUCPW(T), area under curve per weight; 3) total quantum center moment as MCRT(T), mean chromatographic retention time of total quantum, expressed by lambda(T); 4) total quantum variance as VCRT(T), variance of mean chromatographic retention time of total quantum, expressed by sigma2(T), by which we have obtained. The TQSM's parameters of the AELRR, such as AUC(T) as 3.273 x 10(8) microV s, AUCPW(T) as 2.286 x 10(6) microV s mg (-1), MCRT(T) as 33.50 min, VCRT(T) as 484.4 min2, and total quantum concentration as 143.2 mg mL(-1). The total quantum statistic moment can be characterized the curve of chromatographic fingerprints with expressive parameters above, also used to quantitative analyses by AUC(T), to qualitative analyses by AUCPW(T), MCR(T), and VCRT(T).

We identified cytochrome P450 (P450) isozymes that are involved in the formation of two active sibutramine (N-{1-[1-(4-chlorophenyl)-cyclobutyl]-3-methylbutyl}-N,N-dimethylamine) metabolites, M1 (N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine) and M2 (1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine), in humans using a combination chemical inhibition, correlation analyses in human liver microsomes (HLMs), and activity assays using recombinant P450s. Mechanism-based CYP2B6 inhibitors (i.e., clopidogrel, ticlopidine, and triethylenethiophoramide) significantly inhibited the formation of M1 from sibutramine and M2 from M1, respectively; in contrast, no effect was observed when using potent inhibitors of eight P450 isozymes (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A). In addition, the formations of M1 from sibutramine (r = 0.694, p = 0.0029) and M2 from M1 (r = 0.834, p0.0001) were strongly correlated with CYP2B6-catalyzed bupropion hydroxylation in 16 different HLM panels. Furthermore, recombinant CYP2B6 catalyzed M1 and/or M2 formation at the highest rate among 10 P450s. Although recombinant CYP2C19, 3A4, and 3A5 also catalyzed, to a less extent, M1 formation at high substrate concentrations (5 microM), those contributions might be minor considering usual concentrations of sibutramine and M1 in the clinical setting. The kinetics of M1 and/or M2 formation from sibutramine in HLMs were fitted by a two-enzyme model, and the mean apparent K(m) value (4.79 microM) for high-affinity component was similar to that observed in recombinant CYP2B6 (8.02 microM). In conclusion, CYP2B6 is the primary catalyst for the formation of sibutramine two active metabolites, which may suggest that pharmacogenetics and drug interactions of sibutramine in relation to CYP2B6 activity should be considered in the pharmacotherapy of sibutramine.

Background: Rifampicin (rifampin) has been reported to have drug-drug interaction with several 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors due to its ability to influence the function of cytochrome P450 enzymes or transporters. Rosuvastatin is absorbed from the blood into the liver by organic anion transporting polypeptide 1B1 and is then metabolized by cytochrome P450 isozyme 2C9. Objective: The aim of this study was to examine the effect of rifampicin on the pharmacokinetics of rosuvastatin. Methods: This was a randomized, single-blind, placebo-controlled, crossover study, with a 4-week washout period. Healthy male volunteers were treated for 6 days with rifampicin 450 mg or placebo once daily. On days 0 and 7, a single oral dose of rosuvastatin 20 mg was administered. Plasma concentrations of rosuvastatin were measured by liquid chromatography-tandem mass spectrometry. Results: A total of 18 healthy Chinese male volunteers (mean [SD] age, 21 [2] years; weight, 62 [7] kg; and body mass index was within the normal range [22.0-24.0 kg/m2]) were included in the study. The plasma concentrations of rosuvastatin were not significantly changed by pretreatment with rifampicin, although there was considerable interindividual variation in the plasma concentration of rosuvastatin. During the rifampicin phase, the AUC 0-∞ of rosuvastatin decreased in 10 and increased in 8 of the 18 subjects. In 3 of the 8 subjects, the AUC 0-∞ of rosuvastatin during the rifampicin phase was ≥50% compared with the placebo phase; and only 1 increased by more than double (183%). Of those in the decreased group (n = 10), the AUC 0-∞ values were decreased by >50% in 3 subjects and were not decreased by >30% in the remaining 7 subjects. The mean AUC 0-∞ of rosuvastatin was 95.8% (110.4 [41.4] vs 115.3 [30.9] ng/mL · h -1 ) of the corresponding value during the placebo phase ( P = NS). There was no statistically significant difference in either C max or t 1/2 of rosuvastatin between the rifampicin-treated and placebo groups (18.5 [6.3] vs 16.5 [5.5] ng/mL; 12.8 [3.0] vs 13.3 [2.8] h). The oral clearance of rosuvastatin was not significantly affected by rifampicin pretreatment either (0.4 [0.3] vs 0.3 [0.2] L · h; P = 0.072). Conclusion: The pharmacokinetics of rosuvastatin were not significantly changed by coadministration of rifampicin in this small group of healthy male volunteers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Rosiglitazone is able to increase serum adiponectin levels significantly in Type 2 diabetic patients. • The role of genetic factors that determine the marked interindividual variability in glucose-lowering efficacy of rosiglitazone in Chinese patients is not known. • The current study was designed to evaluate the impact of the adiponectin common allele 45T/G and −11377C/G polymorphisms on the response to rosiglitazone monotherapy in Chinese patients with Type 2 diabetes (T2D). WHAT THIS STUDY ADDS • The genetic polymorphisms of adiponectin alleles 45T/G and −11377C/G as well as their common diplotypes are significantly associated with an attenuated fasting plasma glucose, postprandial plasma glucose and homeostasis model assessment for insulin resistance as well as an enhanced adiponectin concentration in Chinese patients with T2D after rosiglitazone treatment. AIMS The aim of the present study was to evaluate the impact of adiponectin allele T45G and C-11377G genetic polymorphisms on efficacy of rosiglitazone in Chinese patients with type 2 diabetes (T2D). METHODS Patients with T2D (n = 255) and 120 healthy volunteers were enrolled to identify 45T/G and –11377C/G genotypes by polymerase chain reaction-restriction fragment length polymorphism assay. Forty-two T2D patients with different 45T/G or –11377C/G genotypes received orally rosiglitazone as a single-dose therapy (4 mg day-1 p.o.) for 12 weeks. Serum triglyceride, fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin, fasting serum insulin, postprandial serum insulin, total cholesterol, homeostasis model assessment for insulin resistance (HOMA-IR), low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol (HDL-c) and adiponectin concentration were determined before and after rosiglitazone treatment. RESULTS We showed an attenuated rosiglitazone effect in patients with –11377CG+GG heterozygote genotype on FPG, PPG, HOMA-IR compared with –11377CC homozygote genotype. However, we found an enhanced rosiglitazone effect on serum adiponectin concentration in patients with –11377CC homozygote genotype compared with –11377CG+GG heterozygote genotype (P = 0.000) and in patients with 45TG + GG heterozygote genotype compared with 45TT homozygote genotype (P = 0.018). Finally, our results showed that there was an enhanced effect in patients with –11377/45 CGTT diplotype compared with other discovered diplotypes on FPG (P = 0.001) and PPG (P = 0.003) after rosiglitazone treatment. CONCLUSIONS These data suggest that the adiponectin allele 45T/G and –11377C/G polymorphisms are significantly associated with the therapeutic efficacy of multiple-dose rosiglitazone in Chinese patients with T2D.

1. Clopidogrel is one of the most important antithrombotic drugs but has different efficacies in different populations. The aim of the present study was to evaluate the contribution of CYP2C19 genetic polymorphisms to the inhibition of ADP-induced platelet aggregation by clopidogrel in healthy Chinese volunteers. 2. Eighteen healthy male volunteers (six CYP2C19*1/CYP2C19*1, six CYP2C19*1/CYP2C19*2and*3 and six CYP2C19*2/CYP2C19*2and*3) were enrolled in the study. Each subject took 300 mg clopidogrel on the first day and then 75 mg once daily for 2 consecutive days. Blood samples were taken to measure ADP-induced platelet aggregation at baseline and 4, 24 and 72 h after administration of the first dose of clopidogrel. 3. There were significant decrease in 2 and 5 micromol/L ADP-induced platelet aggregation at 4, 24 and 72 h after clopidogrel among the three CYP2C19 genotypes compared with baseline (P < 0.001). The change in 5 micromol/L ADP-induced platelet aggregation in subjects with the CYP2C19*1/CYP2C19*1 genotype was greater than that in subjects with the CYP2C19*2/CYP2C19*2and*3 genotype at 4 h (49.0 +/- 15.5 vs 29.7 +/- 17.4%, respectively; P = 0.029), 24 h (48.7 +/- 20.5 vs 25.0 +/- 17.6%, respectively; P = 0.035) and 72 h (45.5 +/- 15.2 vs 26.5 +/- 15.8%, respectively; P = 0.030) after clopidogrel administration. 4. In conclusion, CYP2C19*2 and CYP2C19*3 genetic polymorphisms reduced clopidogrel inhibition of ADP-induced platelet aggregation, with the degree of inhition dependent on the genetic polymorphism present.

Because both quinidine and propranolol bind to the cytochrome P-450 responsible for the oxidation of debrisoquin, six healthy male subjects were studied to determine whether an interaction occurred between the two drugs and the pharmacodynamic consequences of that interaction. The coadministration of quinidine resulted in a doubling of the area under the plasma concentration-time curve of (+/-)-propranolol (530 +/- 99 versus 1051 +/- 138 ng.hr/ml; p less than 0.05) and a reduction in the clearance of (+/-)-propranolol from 3087 +/- 648 to 1378 +/- 173 ml/min (p less than 0.05). The metabolism of propranolol by the 4-hydroxylation pathway was almost abolished by quinidine, resulting in a fall in the partial metabolic clearance by this pathway from 678 +/- 246 to 56 +/- 11 ml/min (p less than 0.05). Quinidine differentially affected the metabolism of (+)-propranolol and (-)-propranolol, resulting in an increase of 176.6% +/- 45.5% and 100.4% +/- 25.5% in the area under the plasma concentration-time curve of (+)-propranolol and (-)-propranolol, respectively (p less than 0.05). The pharmacokinetic changes were associated with pharmacodynamic effects. The combination of propranolol and quinidine resulted in increased beta-blockade measured by reduction in exercise heart rate and prolongation of the QTc and PR intervals. We conclude that quinidine stereoselectively inhibits the metabolism of propranolol through inhibition of the debrisoquin isozyme. The increased concentration of propranolol produced by quinidine results in increased beta-blockade.

We have previously demonstrated that Chinese subjects are more sensitive than white subjects to beta-blockade produced by propranolol. To determine if this difference was because a greater proportion of the total propranolol was the more active (-)-isomer of propranolol in the Chinese subjects than in the white subjects, the relative pharmacokinetics of (+)- and (-)-isomers of propranolol after administration of a single, 80 mg oral dose of racemic propranolol was studied in 10 Chinese male and in 9 white male healthy subjects. The plasma concentrations of both (+)- and (-)-propranolol were lower in Chinese than in white subjects, resulting in significantly lower peak plasma concentrations and areas under the concentration-time curve (AUC) in Chinese subjects, the half-life of elimination did not differ significantly between Chinese and white subjects or between the two isomers. The concentrations of the active (-)-propranolol were higher in both groups of subjects because of the lower clearance of the (-)-propranolol compared with the (+)-propranolol. An excellent correlation between the clearance of (+)- and (-)-propranolol was seen in the same individual. The ratio of AUC of (-)- and (+)-propranolol did not differ between Chinese subjects (0.64 +/- 0.03) and white subjects (0.71 +/- 0.09). The data suggest that the proportion of the two isomers found in Chinese and white subjects did not differ, and therefore differences in stereoselective disposition of propranolol cannot explain the increased sensitivity seen in Chinese individuals.

Aim: To detect 388G>A and 521T>C variant alleles in the organic anion transporting polypeptide-1B1 (OATP1B1, encoding gene SLCO1B1) gene. Methods: One hundred and eleven healthy volunteers were screened for OATP1B1 alleles in our study. PCR-restriction fragment length polymorphism was used to identify the 388G>A polymorphism and a 1-step tetra-primer method was developed for the determination of 521T>C mutation. Results: The frequencies of the 388G>A and 521T>C variant alleles in the Chinese population were 73.4% and 14.0%, respectively. The frequencies of the SLCO1B1*1 b and *15 haplotypes were 59.9% and 14.0%, respectively. Conclusion: The SLCO1B1*1 b and SLCO1B1*15 variants are relatively common in the Chinese population. Their frequencies are similar to that in the Japanese, but significantly different from that in Caucasians and blacks.