Review of the in vitro inhibitory effects of traditional Chinese medicine and its components on CYP450 enzymes in liver microsomes / 药学学报

Cytochrome P450s (CYP450) is a superfamily of phase I metabolic enzymes, which participates in more than 90% of drug oxidation. The induction or inhibition of CYP450s is the main mechanism of drug-drug interaction. In recent years, in vitro metabolism studies conducted through isolated organs, cells, or enzyme systems have developed rapidly, due to their precision and simplicity. Therefore, profiles of the in vitro metabolism studies of traditional Chinese medicines can infer the possible metabolic pathways of drugs, predict the potential drug interactions, and may enhance the rational use of drugs in clinic. This article reviews the in vitro inhibitory effects of traditional Chinese medicine, ingredients, and extracts on the activities of CYP450 enzymes in the liver microsomes, which can provide a reference for further researches on the interaction between Chinese medicine and chemical medicine.

Changes of pharmacokinetics and application of physiologically based pharmacokinetic modeling in pharmacotherapy during pregnancy / 药学学报

The rational medication in pregnant women is a clinical issue that clinicians and pharmacists must take seriously. Most tissues and organs undergo anatomical and physiological changes during pregnancy that affect the absorption, distribution, metabolism, and excretion of drugs in vivo, which ultimately lead to changes in bioavailability. In order to achieve an effective therapeutic concentration, dose adjustment might be required during this period. In the past ten years, the application of modeling and simulation methods in the field of drug development and clinical therapy has continued to expand, for instance, using population pharmacokinetic (PPK) and physiologically based pharmacokinetic (PBPK) modeling to adjust dosage regimen in special populations. Rigorously designed and validated models will effectively make up for the deficiencies of clinical trials, provide valuable references for the design of clinical research, and even replace part of them. This article will introduce the physiological changes that affect the pharmacokinetic properties of the drug during pregnancy and review the progress in the application of PBPK modeling in pharmacokinetic studies in pregnant women.

Enhancement of oral bioavailability and immune response of Ginsenoside Rh2 by co-administration with piperine / 中国天然药物

Ginsenoside Rh2 (Rh2) is one of the major bioactive ginsenosides in Panax ginseng. However, the oral bioavailability of Rh2 is low, with P-glycoprotein (P-gp) and CYP3A4 being reported to be the main factors. The purpose of the present study was to determine the enhancing effect of piperine on the oral bioavailability as well as bioactivity of Rh2. The inhibitory effect of piperine on P-gp and CYP3A4 was determined using a Caco-2 monolayer model and a recombinant CYP3A4 metabolic system, respectively. The pharmacokinetics of oral Rh2 (10 mg·kg) administered alone or in combination with piperine (10 and 20 mg·kg) was performed in rats. The immune boosting effect of Rh2 was assessed in rats by measuring IL-12 level after treated by Rh2 alone or co-administered with piperine. The results indicated that piperine significantly increased the permeability of Rh2 and inhibited the metabolism of Rh2. The pharmacokinetic study results showed that the AUC of Rh2 was significantly increased in combination with piperine at high dose (20 mg·kg) when compared to the control group, with relative bioavailability of 196.8%. The increase of Rh2 exposure led to increased serum levels of IL-12. In conclusion, piperine may be used as a bioenhancer to improve pharmacological effect of Rh2 when given orally.

Enhancement of oral bioavailability and immune response of Ginsenoside Rh2 by co-administration with piperine / 中国天然药物

Ginsenoside Rh2 (Rh2) is one of the major bioactive ginsenosides in Panax ginseng. However, the oral bioavailability of Rh2 is low, with P-glycoprotein (P-gp) and CYP3A4 being reported to be the main factors. The purpose of the present study was to determine the enhancing effect of piperine on the oral bioavailability as well as bioactivity of Rh2. The inhibitory effect of piperine on P-gp and CYP3A4 was determined using a Caco-2 monolayer model and a recombinant CYP3A4 metabolic system, respectively. The pharmacokinetics of oral Rh2 (10 mg·kg) administered alone or in combination with piperine (10 and 20 mg·kg) was performed in rats. The immune boosting effect of Rh2 was assessed in rats by measuring IL-12 level after treated by Rh2 alone or co-administered with piperine. The results indicated that piperine significantly increased the permeability of Rh2 and inhibited the metabolism of Rh2. The pharmacokinetic study results showed that the AUC of Rh2 was significantly increased in combination with piperine at high dose (20 mg·kg) when compared to the control group, with relative bioavailability of 196.8%. The increase of Rh2 exposure led to increased serum levels of IL-12. In conclusion, piperine may be used as a bioenhancer to improve pharmacological effect of Rh2 when given orally.

Advances in the research of pharmacogenomics of tamoxifen / 药学学报

Tamoxifen (TAM) is the most common nonsteroidal antiestrogen agent, which has been widely used in the prevention of recurrence of estrogen or progesterone receptor-positive breast cancer in patients. It is metabolized by cytochrome P450 oxidases to its active metabolite (4-hydroxytamoxifen, 4-OH-TAM) and endoxifen (EDF), which played a critical role in the therapy. 4-OH-TAM and EDF have 30-to 100-fold more potency than TAM in the suppression of estrogen-dependent breast cancer cell proliferation. CYP3A4 and CYP2D6, as the key drug-metabolizing enzymes in those metabolic actions, are known to have several alleles. Genetic polymorphisms of CYP2D6 and CYP3A4 will influence the plasma concentrations of active TAM metabolites and clinical outcomes for breast cancer patients treated with TAM. The genetic polymorphisms of drug transporters, involved in the disposition of active TAM metabolites, also have the potential to influence the plasma concentrations of active TAM metabolites and clinical outcome for the treatment of breast cancer. In this review, we summarized the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the metabolism and disposition of TAM with the metabolite concentration, efficacy and adverse effects of TAM, which provides a fundamental reference for further pharmacogenomic study and clinical use of TAM.

Transplacental transport mechanisms of drugs for transplacental treatment of fetal tachyarrhythmia of MDCKII/MDCKII-BCRP cell line / 药学学报

To study the transport mechanisms of drugs for transplacental treatment of fetal tachyarrhythmia, MDCKII-BCRP and MDCKII cell models was used. MDCKII-BCRP and MDCKII cell monolayer model was used to investigate the bi-direction transport of sotalol, propranolol, propafenone, procainamide and flecainide. Drug concentrations were measured by HPLC-UV or chemiluminescence. The apparent permeability coefficient (P(app)), efflux rate (R(E)) and net efflux rate (R(net)) were calculated. Drugs with R(net) greater than 1.5 were further investigated using cellular accumulation experiments with or without a BCRP inhibitor. The R(net) of sotalol, propranolol, propafenone and procainamide were less than 1.5, while R(net) of flecainide with concentrations of 20 and 5 μmol x L(-1) were 1.6 and 1.9, respectively. The results showed that the transport of flecainide on MDCKII-BCRP cell monolayer could be mediated by BCRP; and the affinity increased when the concentration of flecainide decreased. Cellular accumulation experiments further suggested that accumulation of flecainide in MDCKII-BCRP cells was significantly lower than that in MDCKII cells in a concentration-dependent manner. BCRP inhibitor quercetin (50 μmol x L(-1)) significantly increased the accumulation of flecainide in MDCKII-BCRP cells (P < 0.05). Our preliminary data showed that flecainide but not sotalol, propranolol, propafenone or procainamide can be a substrate of BCRP. Thus the effect of flecainide may be affected by the BCRP in the maternal placental trophoblast membrane layer when treating fetal tachyarrhythmia.

Enhancers on the transmembrane transport of chlorogenic acid / 药学学报

To investigate the influence of the difference enhancers on the transport mechanism of chlorogenic acid (CGA) across Caco-2 cells model, a RP-HPLC method was adopted to detect the concentrations of CGA. At the concentrations of 20 to 80 microg x mL(-1), the difference of absorption rate constants (K(a)) was not statistically significant. At the concentrations of 40 and 20 microg x mL(-1), the ratios of apparent permeability coefficients (P(app)) of the apical to basolateral and the basolateral to apical were 1.14 and 1.18, respectively. With the effect of enhancers K(a) and P(app) increased, the absorption half-life (T1/2) decreased. CGA passed through the Caco-2 cell membrane mainly by passive transport. It showed that monocarboxylic acid transporter (MCT) could be involved in the across membrane transport process of CGA. Borneol had no effect on the cell membrane transport processes. The order of increasing absorption of CGA caused by the enhancers was sodium lauryl sulphate > sodium taurocholate > carbomer.

Effect of Kangshuai Yizhi Formula I on learning and memory dysfunction induced by scopolamine in mice / 中国结合医学杂志

<p><b>OBJECTIVE</b>To evaluate the improvement of Kangshuai Yizhi Formula I ( I, KYF I) on: the learning and memory dysfunction in mice, and on the mechanism of the hippocampal cholinergic system and the nervous system of monoamine which are closely related to learning and memory function.</p><p><b>METHODS</b>Mice: in the low-, middle-, and high-dose KYF I groups were given low-, middle-, and high-dose KYF, respectively, by gastrogavage for 35 successive days. Animals in the control group and the model group were treated with distilled water. The acute learning and memory dysfunction model was established by injection of scopolamine from day 31, and Morris water maze was used to assess the behavior performance of scopolamine-induced model mice for five days. The activities of acetylcholinesterase (AChE), choline acetyl transferase (ChaT) and the content of monoamine neurotransmitters in hippocampus were measured. The activity of monoamine oxidase (MAO) in hippocampus and serum was also detected.</p><p><b>RESULTS</b>(1) Compared with the control group, the: mean escape latency was shortened, and the frequency across the platform and the staying time at the platform area on the 5th day were decreased in the model group by Morris water maze test. The activities of AChE and MAO were increased, and the ChaT activity and monoamine neurotransmitter content were decreased as well. (2) The escape latency for 4 days in the low-, middle-, and high-dose KYF I groups was significantly shortened than that in the model group, with the shortest latency in the high-dose KYF I group (P<0.05, P<0.01). The frequency across the platform was significantly increased and the staying time at the platform was significantly prolonged in the middle- and high-dose KYF I groups (P<0.05, P<0.01). (3) As compared with the model group, the activity of ChaT and the content of monoamine neurotransmitters in the hippocampus were significantly increased, and the activities of AchE and MAO were significantly decreased in the hippocampus in the high-dose KYF I group (P<0.01).</p><p><b>CONCLUSIONS</b>High-dose KYF I can significantly improve the learning and memory dysfunction: induced by scopolamine in mice. Its mechanism may be related to improving the central cholinergic system and regulating the hippocampal monoamine neurotransmitters.</p>

Investigation on pharmacokinetics of helicid in rats / 中国中药杂志

<p><b>OBJECTIVE</b>To report the pharmacokinetic parameters of helicid HD in rats after intravenous administration at different doses.</p><p><b>METHOD</b>Fifteen Wistar rats were randomly assigned as three groups (n=5, male) to be given helicid solution via tail vein injection at a single dose of 2.23, 4.46, 6.70 mg x kg(-1), respectively. Blood samples were collected via tail vein at time intervals after HD injection. 6% perchloric acid was to precipitate plasma protein. Separation was achieved on a reversed-phase C18 column with UV detection at 270 nm.</p><p><b>RESULT</b>The calibration curves were linear ranging from 43.8 to 43,800 microg x L(-1). The intra-and inter-day precisions were no more than 6%. The average recovery of helicid was more than 87% from plasma. With minimum akaike information criterion (AIC) values, a two-compartment open pharmacokinetic model was proposed and validated through the DAS 2.0 to explain the apparent diphasic phenomenon of (HD) in rat blood after intravenous administration. Helicid appeared to be distributed rapidly into a highly perfused central compartment (first compartment), with a less rapidly elimination. The diphasic phenomenon could be observed from the compartment model parameters t(1/2alpha) and t(1/2beta). The least squares regression analysis indicated that the plasma concentrations and AUC of helicid in rat plasma were proportional to the administrated doses. At the administrated doses of 2.23, 4.46, 6.70 mg x kg(-1), the values of distribution half-life (t(1/2alpha)) were 4.582, 5.097, 4.727 min, respectively. And the values of elimination half-life (t(1/2beta)) were 23.945, 26.508 and 25.396 min, respectively. The volume of distribution from these three different doses were 0.036, 0.035, 0.035 L, respectively. The AUCo(0-->t) (area under the concentration-time curve) increase was proportional to the administrated dose.</p><p><b>CONCLUSION</b>In the range of the doses examined, the pharmacokinetics of helicid in rats is based on linear dynamics.</p>

Studies on the absorption kinetics of baicalin and baicalein in rats' stomachs and intestines / 中国中药杂志

<p><b>OBJECTIVE</b>To study the absorption kinetics of baicalin and baicalein in rats' stomachs and intestines.</p><p><b>METHOD</b>The drug concentration by in situ perfusion in rats were determined by HPLC.</p><p><b>RESULT</b>The hourly absorption percentages of baicalin in stomach, small intestine and colon were 8.05%, - 0.94% and 2.32%, respectively, and baioalein with 34.53%, 30.61% and 4.89%, respectively. The absorption rate constants of baicalein were 0.090 7, 0.083 7, 0.076 6 and 0.048 3, respectively in duodenum, jejunum, ileum and colon.</p><p><b>CONCLUSION</b>Baicalin is moderately absorbed in stomach and poorly in small intestine and colon; Baicalein is well absorbed in stomach and small intestine but worse in colon, suggesting that the former is more suitable to be administered orally. The extensive absorption segments of bacailein suggests that it can be processed into a sustained-release preparation.</p>

Determination of octreotide in human plasma by HPLC-MS with solid-phase extraction and study on the relative bioavailability of domestic and imported octreotide injections / 药学学报

<p><b>AIM</b>To establish an HPLC-MS method for determination of octreotide in plasma and study the relative bioavailability of domestic and imported octreotide injections.</p><p><b>METHODS</b>Octreotide in plasma samples were extracted with a Waters solid-phase extraction mini column. HPLC-MS was carried out using a Waters Xetrra C18 column and a mobile phase consisting of CH3 OH-1% HAc (80 : 20), the flow rate was 0.2 mL x min(-1), and the internal standard was 6, 7, 4'-OH-isoflavone, the SIR ions for quantification were m/z 1 014.4 for octreotide and m/z 317.6 for internal standard. A single dose of 200 microg of domestic or imported preparations was intramuscularly given to 18 healthy volunteers in a randomized crossover study. Octreotide concentration in plasma was determined by LC-MS method. The pharmacokinetics and bioavailability were studied.</p><p><b>RESULTS</b>The regressive curve was linear (r = 0.9997) within the range of 0.5 - 40 microg x L(-1) for octreotide. The pharmacokinetics parameters of domestic and imported injection were reply to one compartment model. The mean C(max) were (19 +/- 10) microg x L(-1) and (19 +/- 11) microg x L(-1), T(max) were (0.50 +/- 0.15) h and (0.52 +/- 0.20) h, T1/2 were (1.5 +/- 0.8) h and (1.5 +/- 0.8) h, AUC(0-7 h) were (50 +/- 25) h x microg x L(-1) and (50 +/- 25) h x microg x L(-1), respectively. The relative bioavailability of domestic to imported injection was 101% +/- 10%.</p><p><b>CONCLUSION</b>The method is accurat and sensible for assay of plasma octreotide concentration. The results of statistics showed the two preparations were bioequivalent.</p>

Study on the pharmacokinetics of scutellarin in dogs / 药学学报

<p><b>AIM</b>To determine scutellarin in dog plasma and study the pharmacokinetics of scutellarin in the dog.</p><p><b>METHODS</b>Scutellarin in plasma of six dogs at different sampling time was determined after single dose of 120 mg i.v. by RP-HPLC. The mean plasma concentration-time curve was protracted and pharmacokinetic parameters were calculated.</p><p><b>RESULTS</b>The concentration-time curve of scutellarin can be fitted to a three-compartment model with the main pharmacokinetic parameters as follows: T1/2 gamma, T1/2 alpha and T1/2 beta were (1.1 +/- 0.8) min, (7.0 +/- 2.8) min and (52 +/- 29) min, respectively, Vc was (880 +/- 508) mL, CL was (190 +/- 54) mL.min-1, AUC0-90 and AUC0-infinity were (574 +/- 134) mg.min.L-1 and (559 +/- 132) mg.min.L-1 respectively.</p><p><b>CONCLUSION</b>The concentration of scutellarin in plasma declined rapidly after single dose of 120 mg i.v. in dogs, and this suggested that the T1/2 of scutellarin should be taken into account in preparation exploitation and drug administration.</p>