Xijing Chen

China Pharmaceutical University, Nan-ching-hsü, Jiangxi Sheng, China

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Publications (67)145.99 Total impact

  • Yi Zheng · Xijing Chen · Leslie Z Benet ·
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    ABSTRACT: As the effect of P-glycoprotein (P-gp) transport on antidepressant delivery has been extensively evaluated using in vitro cellular and in vivo rodent models, an increasing number of publications have addressed the effect of P-gp in limiting brain penetration of antidepressants and causing treatment-resistant depression in current clinical therapies. However, contradictory results have been observed in different systems. It is of vital importance to understand the potential for drug interactions related to P-gp at the blood-brain barrier (BBB), and whether coadministration of a P-gp inhibitor together with an antidepressant is a good clinical strategy for dosing of patients with treatment-resistant depression. In this review, the complicated construction of the BBB, the transport mechanisms for compounds that cross the BBB, and the basic characteristics of antidepressants are illustrated. Further, the reliability of different systems related to antidepressant brain delivery, including in vitro bidirectional transport cell lines, in vivo Mdr1 knockout mice, and chemical inhibition studies in rodents are analyzed, supporting a low possibility that P-gp affects currently marketed antidepressants when these results are extrapolated to the human BBB. These findings can also be applied to other central nervous system drugs.
    Clinical Pharmacokinetics 08/2015; DOI:10.1007/s40262-015-0310-2 · 5.05 Impact Factor
  • Qiuyang Zhang · Wei Yang · Qing Zhang · Yue Yang · Junxiu Li · Yang Lu · Yi Zheng · Jiake He · Di Zhao · Xijing Chen ·
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    ABSTRACT: An enantioselective high-performance liquid chromatography method was developed and validated for the determination of oxiracetam enantiomers, a cognition and memory enhancer, in beagle dog plasma. The plasma samples were prepared by methanol extraction from 200μL plasma, and then the baseline resolution was achieved on a Chiralpak ID column (250mm×4.6mm, 5μm) with mobile phase of hexane-ethanol-trifluoroacetic acid (78:22:0.1, v/v/v) at flow rate of 1.0mL/min. The column elute was monitored using ultraviolet detection at 214nm. The method was linear over concentration range 0.50-100μg/mL for both enantiomers. The relative standard deviation values for intra- and inter-day precision were 0.78-13.61 and 0.74-8.92% for (R)- and (S)-oxiracetam, respectively. The relative error values of accuracy ranged from -4.74 to 10.48% for (R)-oxiracetam and from -0.19 to 11.48% for (S)-oxiracetam. The method was successfully applied to a pharmacokinetic study of individual enantiomer and racemic oxiracetam in beagle dogs after oral administration. The disposition of the two enantiomers was not stereoselective and chiral inversion was not observed in beagle dogs. The pharmacokinetic profiles of (S)-oxiracetam were similar with racemic oxiracetam in beagle dogs. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 04/2015; 993-994C:9-13. DOI:10.1016/j.jchromb.2015.04.033 · 2.73 Impact Factor
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    ABSTRACT: Oxiracetam (ORC), a nootropic drug used for improving the cognition and memory, has an asymmetric carbon in its structure and exists as (S)- and (R)-ORC. The pharmacokinetic profiles of racemic oxiracetam and its pure enantiomers in rats were evaluated and compared by enantioselective high-performance liquid chromatography, which was performed on a Chiralpak ID column with a mobile phase of hexane-ethanol-trifluoroacetic acid (78:22:0.1, v/v/v). The method was validated with respect to selectivity, linearity, accuracy and precision, stability and the limit of quantification. The validation acceptance criteria were met in all cases. A saturating phenomenon of (S)-ORC was observed when the dosage ranged from 200mg/kg to 800mg/kg. The two enantiomers showed similar profiles in the absorb phase, and reached the maximum concentration at 2h after oral administration. However, compared with the racemate group, the AUC/dose and Cmax/dose ratios of (S)-ORC were higher and Cl/f was lower in enanpure (S)-ORC group. The Cmax of (S)-ORC decreased from 21.3±5.0μg/ml to 13.2±4.2 when (R)-ORC was co-administrated at the dose of 200mg/kg. AUC0-t values of (S)-ORC were different after oral administration of 200mg/kg (S)-ORC and 400mg/kg racemic ORC (96.7±15.5 and 50.1±16.3μgh/ml). The higher absorption and slower elimination suggest that enantiopure (S)-ORC could be a promising drug that efficiently reduces clinical dosage, improves therapeutic indices, decreases toxicology risks, and results in increased therapeutic ration. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of pharmaceutical and biomedical analysis 04/2015; 111:153-158. DOI:10.1016/j.jpba.2015.03.039 · 2.98 Impact Factor
  • Yi Zheng · Leslie Z Benet · Hideaki Okochi · Xijing Chen ·
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    ABSTRACT: Recent controversial publications, citing studies purporting to show that P-gp mediates the transport of propranolol, proposed that passive biological membrane transport is negligible. Based on the BDDCS, the extensively metabolized-highly permeable-highly soluble BDDCS class 1 drug, propranolol, shows a high passive permeability at concentrations unrestricted by solubility that can overwhelm any potential transporter effects. Here we reinvestigate the effects of passive diffusion and carrier-mediated transport on S-propranolol. Bidirectional permeability and inhibition of efflux transport studies were carried out in MDCK, MDCK-MDR1 and Caco-2 cell lines at different concentrations. Transcellular permeability studies were conducted at different apical pHs in the rat jejunum Ussing chamber model and PAMPA system. S-propranolol exhibited efflux ratios lower than 1 in MDCK, MDCK-MDR1 and Caco-2 cells. No significant differences of Papp, B->A in the presence and absence of the efflux inhibitor GG918 were observed. However, an efflux ratio of 3.63 was found at apical pH 6.5 with significant decrease in Papp, A->B and increase in Papp, B->A compared to apical pH 7.4 in Caco-2 cell lines. The pH dependent permeability was confirmed in the Ussing chamber model. S-propranolol flux was unchanged during inhibition by verapamil and rifampin. Furthermore, pH dependent permeability was also observed in the PAMPA system. S-propranolol does not exhibit active transport as proposed previously. The "false" positive efflux ratio can be explained by the pH partition theory. As expected, passive diffusion, but not active transport, plays the primary role in the permeability of the BDDCS class 1 drug propranolol.
    Pharmaceutical Research 02/2015; 32(8). DOI:10.1007/s11095-015-1640-3 · 3.42 Impact Factor
  • Zhixia Qiu · Lei Wang · Yu Dai · Weichao Ren · Wenwen Jiang · Xijing Chen · Ning Li ·
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    ABSTRACT: Ginkgolide B (GB) is a selective and strong antagonist of platelet-activating factor with great benefits in CNS diseases treatment. The renal excretion constitutes the predominant secretory pathway of GB. Here, we investigated the potential role of renal drug transporters in GB urinary excretion. The intravenous administration of GB was conducted at 10 min post-administration of probenecid (potential inhibitor of organic anion transporters/organic anion transporting polypeptides) or bromosulfophthalein (traditional inhibitor of multi-drug resistance proteins) in rats. Pretreated with probenecid, the systemic exposure of GB was significantly elevated from 8.319 ± 1.646 to 14.75 ± 1.328 µg · mL−1∙h but with reduced total clearance from 1.17 ± 0.331 to 0.596 ± 0.0573 L · h−1∙kg−1 accompanying no changes in plasma elimination half-lives compared with control group. With no pronounced effect on metabolic elimination, the decreased total clearance was closely pertained to the reduced renal excretion, indicating the potential effect of organic anion transporters and/or organic anion transporting polypeptides in renal secretory of GB from blood to urine. However, the possible effect of bromosulfophthalein was restricted within a minor extent, suggesting the mild role of multi-drug resistance protein in GB renal excretion. Copyright © 2015 John Wiley & Sons, Ltd.
    Phytotherapy Research 01/2015; 29(5). DOI:10.1002/ptr.5294 · 2.66 Impact Factor
  • Qiuyang Zhang · Wei Yang · Hanlin Song · Hui Wu · Yang Lu · Jiake He · Di Zhao · Xijing Chen ·
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    ABSTRACT: Multidrug resistance protein 2 (Mdr2), encoded by ATP-binding cassette b4 (Abcb4), serves as a phospholipid flippase that is indispensable for phosphatidylcholine translocation. However, little was known about the regulation of Mdr2 in Sprague-Dawley rats, although they are commonly used for pre-clinical investigation as well as mechanistic study. Present study aims at determining the tissue distribution, gender difference and ontogeny of Mdr2 in rats on both gene and protein levels. Results showed that Mdr2 was highly expressed in liver, modestly enriched in brain and testis, and less distributed in gastrointestinal tracts. Gender-divergent and male-dominated distribution was observed in the Mdr2 mRNA expression of liver and generative organs. Developmental pattern of rat Mdr2 on protein level was not exactly consistent with that on mRNA level. In conclusion, there was a considerable distribution of rat Mdr2 in the brain, testis and intestine besides liver, and the ontogeny of Mdr2 performed in an age-dependent pattern with the post-transcriptional regulation.
    European Journal of Drug Metabolism and Pharmacokinetics 10/2014; DOI:10.1007/s13318-014-0226-5 · 1.56 Impact Factor
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    ABSTRACT: 1-Triacontanol (TA), a member of long chain fatty alcohol, has recently been received great attention owing to its antitumor activity. In this study, an accurate, sensitive and selective gas chromatography–tandem mass spectrometry method was developed and validated for the quantification of TA in beagle plasma using 1-octacosanal as the internal standard (IS) for the first time. With temperature programming, chromatographic separation was carried out on an HP-5MS column, using helium as carrier gas and argon as collision gas, both at a flow rate of 1 mL/min. TA was analyzed using positive ion electrospray ionization in multiple-reaction monitoring mode, with the precursor to product ion transitions of m/z 495.6 97.0 and m/z 467.5 97.0 for TA and the IS, respectively. The lower limit of quantitation, linearity, intra- and interday precision, accuracy, stability, extraction recovery and matrix effect of TA were within the acceptable limits. The validated method was successfully applied to a pharmacokinetic study of TA in beagles. Copyright © 2014 John Wiley & Sons, Ltd.
    Biomedical Chromatography 10/2014; 29(5). DOI:10.1002/bmc.3351 · 1.72 Impact Factor
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    ABSTRACT: 1. Guanfacine is a selective α2A-adrenoreceptor agonist primarily excreted as its unchanged form through urine in human. This study was to investigate the involvement of organic cation transporter 2 (OCT2) in the renal tubular secretion of guanfacine. 2. Transport of guanfacine was characterized using human embryonic kidney (HEK293) cells expressing human OCT2 (hOCT2). The inhibitory effect of cimetidine on guanfacine uptake was also examined. In addition, in vivo pharmacokinetic study was conducted in rats to assess the effects of cimetidine on the pharmacokinetics of guanfacine. 3. The accumulation of guanfacine in hOCT2-transfected HEK293 cells was both time- and concentration-dependent, and markedly higher than that in mock cells. The apparent Km and Vmax values of guanfacine uptake by hOCT2 were 96.19 ± 7.49 μM and 13.03 ± 0.49 nmol/mg protein/min, respectively. Guanfacine transport mediated by hOCT2 was significantly inhibited by a typical OCT2 inhibitor cimetidine with an IC50 value of 93.82 ± 1.13 μM. Co-administration of cimetidine significantly decreased the plasma clearance (CLp) as well as the renal clearance (CLr) of guanfacine in rats in a dose-dependent manner, resulting in a noticeable increase in the systemic exposure of guanfacine. 4. These results indicated that OCT2 may be involved in the renal disposition of guanfacine.
    Xenobiotica 08/2014; 45(1). DOI:10.3109/00498254.2014.949904 · 2.20 Impact Factor
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    ABSTRACT: 1. 1-Triacontanol (TA) recently shows promising anti-tumor activity. The present study was aimed to develop a sensitive gas chromatography-tandem mass spectrometry method to explore the pharmacokinetic profiles, distribution and excretion of TA in Sprague-Dawley rats after oral administration of TA. Chromatography separation was performed on a HP-5MS column. 1-Octacosanal was used as the internal standard (IS). Quantification of TA and IS was carried out at m/z 495.6 → 97.0 and m/z 467.5 → 97.0, respectively, in positive electron ionization and multiple reaction monitoring mode. The pharmacokinetic parameters were calculated by non-compartmental analysis. 2. The area under concentration-time curve AUC0–6 h and AUC0–∞ for TA at 60 mg/kg were 87.737±13.574 and 93.617±17.62, respectively. The mean residence time was 3.25 ± 0.17 h. In addition, the elimination half-lives (t1/2) were (2.37±1.23, 1.27±0.49, 2.07±0.93) h after single oral administration of 30, 60 and 120 mg/kg of TA. After oral administration, TA was extensively distributed in stomach and intestine. The majority of TA excreted via feces, and its accumulative excretion ratio during the period of 72 h was 26.68 ± 7.14%, but only 0.0023 ± 0.0015% and 0.0027 ± 0.0006% for urines and bile, respectively. The absolute bioavailability (F, %) of TA was about 2.0%.
    Xenobiotica 07/2014; 45(1). DOI:10.3109/00498254.2014.943334 · 2.20 Impact Factor
  • Shuoye Yang · Zhixia Qiu · Qiuyang Zhang · Jiayin Chen · Xijing Chen ·
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    ABSTRACT: The present study investigated the effect of calf thymus DNA (ctDNA) on human hepatic cytochrome P450s (CYP450s) in vitro. Specific substrate probes for each isoform, CYP1A2, 2C9, 2C19, 2D6 and 3A4, were incubated using pooled human liver microsomes with or without ctDNA, and liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) method was developed for the analysis of probe metabolites. Enzyme kinetics parameters K-i and IC50 values were estimated to determine the types and strength of inhibition. ctDNA could specifically inhibit the metabolism of CYP2C9 probe substrates, with the IC50 = 0.9955 mu g/ml, while it was not able to inhibit CYP1A2, CYP2C19, CYP2D6 or CYP3A4 (IC50 > 100 pg/ml). The results showed that ctDNA was a potent inhibitor of CYP2C9 enzyme, and has the metabolic interaction potential with the model drugs which are metabolism substrates of CYP2C9. The inhibition mechanism study suggested ctDNA may inhibit CYP2C9 by decreasing the activity of CYP450 reductase. These findings indicated that when the medical agents catalyzed mainly by CYP2C9 were co-administered in vivo with adsorptive material in vitro, the potential inhibitory effect of ctDNA on enzyme activity and the following metabolism character changes of the former should be highly focused on.
    Drug Metabolism and Pharmacokinetics 07/2014; 29(6). DOI:10.2133/dmpk.DMPK-13-RG-131 · 2.57 Impact Factor
  • Jiake He · Yang Yu · Bhagwat Prasad · Xijing Chen · Jashvant D Unadkat ·
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    ABSTRACT: We have reported an unusual, but clinically significant, digoxin (DIG)-bupropion (BUP) drug interaction (DDI), where BUP increased DIG renal clearance by 80%. To investigate the mechanism(s) of this unusual DDI, we first determined the effect of BUP, its circulating metabolites or their combination on [(3) H]-DIG transport by cells expressing human P-gp or human OATP4C1. Second, we asked whether this DDI could be replicated in the rat so that it could be used to conduct mechanistic studies. Then, we tested the effect of BUP and its rat metabolites on [(3) H]-DIG transport by cells expressing rat Oatp4c1. BUP and its metabolites had no effect on human P-gp mediated transepithelial transport of [(3) H]-DIG. BUP and hydroxybupropion (HBUP) significantly stimulated H-OATP4C1 mediated transport of [(3) H]-DIG. And BUP cocktail (BUP plus its metabolites) significantly increased H-OATP4C1 mediated transport of [(3) H]-DIG, and partially reversed the inhibition by 100 μM DIG. However, erythro-hydrobupropion (EBUP) and threo-hydrobupropion (TBUP) did not affect [(3) H]-DIG uptake by H-OATP4C1 cells. BUP administration significantly increased DIG renal clearance in rats. Surprisingly, BUP significantly inhibited r-Oatp4c1 mediated transport of [(3) H]-DIG at clinically relevant unbound plasma concentrations of BUP or those observed in rat study, while HBUP or TBUP did not. These data support our hypothesis that at clinical relevant plasma concentrations, BUP and its metabolites activate H-OATP4C1 mediated DIG tubular secretion, and could possibly explain the increase in DIG renal clearance produced by BUP. While BUP increased DIG renal clearance in the rat, it appeared to do so by inhibiting r-Oatp4c1-mediated DIG renal reabsorption. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 07/2014; 35(5). DOI:10.1002/bdd.1890 · 2.34 Impact Factor
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    ABSTRACT: Unlabelled: A novel positron emission tomography (PET) tracer, [(11)C]-rosuvastatin (RSV), was developed to dynamically and noninvasively measure hepatobiliary transport and tissue distribution of [(11)C]-RSV in rats. Methods: Male Sprague-Dawley rats were administered either an Oatp inhibitor, rifampin (RIF, 40 mg/kg iv bolus plus 1.85 mg/min/kg iv infusion, n = 3), or the corresponding vehicle (saline, n = 3) for at least 90 min. Then, while these infusions were ongoing, the animals received [(11)C]-rosuvastatin (∼1 mCi/30 s, iv infusion). After [(11)C]-RSV administration, the lower abdominal region of the rats was imaged for 90 min. Time-activity curves for liver, intestine, and kidney were obtained and corrected for vascular content prior to noncompartmental and compartmental (five-compartment model) analysis. Results: The majority of the [(11)C]-RSV dose was distributed into the liver. In the presence of RIF, the area under the [(11)C]-RSV radioactivity blood concentration-time profile (AUC0-90 min) was increased by ∼3-fold. Relative to the control animals, RIF reduced the distribution of [(11)C]-RSV radioactivity into the liver and kidney (tissue AUC0-15 min/blood AUC0-15 min) by 54% and 73% respectively. Compartmental modeling showed that RIF decreased CLBL, CLLI, CLBK, and CLK0 but had no effect on CLLB, where B, L, I, K, and 0 represent blood, liver, intestine, kidney, and irreversible loss. Conclusion: [(11)C]-RSV can be used to dynamically and noninvasively quantify hepatobiliary transport and hepatic concentration of the drug, in the absence and presence of drug interactions, in rats and could be used for the same purpose in humans.
    Molecular Pharmaceutics 06/2014; 11(8). DOI:10.1021/mp500027c · 4.38 Impact Factor
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    ABSTRACT: Liquorice is a commonly prescribed herb in traditional Chinese medicine with the primary constituent, glycyrrhetinic acid (GA) responsible for the toxic effects arising from its chronic consumption. Hepatic transformation and biliary excretion of GA are significant and well-documented pharmacokinetic pathways in humans, while glucuronide conjugates are the major identified metabolites. Here we report the role of bile in GA bioconversion in rats; this being achieved following intravenous administration of GA to Sprague–Dawley rats at a dose of 2 mg/kg with bile fluid analyzed for 3 h post-injection using HPLC. The maximum concentration of glucuronides was detected about 30 min post-administration, while the cumulative biliary excretion of glucuronides after 3 h was found to be 63.6 ± 6.4%. Our findings indicate a relatively high rate of biliary excretion for GA via the formation of glucuronide conjugates, and as a result of these findings, glucuronidation can be firmly regarded as a primary detoxification pathway for GA in rats. Copyright © 2014 John Wiley & Sons, Ltd.
    Phytotherapy Research 05/2014; 28(12). DOI:10.1002/ptr.5170 · 2.66 Impact Factor
  • Amer Talbi · Di Zhao · Qingwang Liu · Junxiu Li · Ali Fan · Wei Yang · Xing Han · Xijing Chen ·
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    ABSTRACT: Wogonin is a natural anticancer candidate. The purpose of this study was to explore the pharmacokinetic profiles, tissue distribution, excretion and plasma protein binding of wogonin in Sprague-Dawley rats. A rapid, sensitive, and specific LC-MS/MS method has been developed for the determination of wogonin in different rat biological samples. After i.v. dosing of wogonin at different levels (10, 20 and 40 mg/kg) the elimination half-life was approximately 14 min, the AUC0-∞ increased in a dose disproportional manner from 112.13 mg/L·min for 10 mg/kg to 758.19 mg/L·min for 40 mg/kg, indicating a non linear pharmacokinetic profile. After i.g. dosing at 100 mg/kg, plasma levels of wogonin peaked at 28 min with a Cmax value of 300 ng/mL and a very low oral bioavailability (1.10%). Following i.v. single dose (20 mg/kg), wogonin was detected in all examined tissues (including testis) with the highest levels in kidney and liver. Approximately 21% of the administered dose was excreted as unchanged drug (mainly via non-biliairy fecal route (16.33%). Equilibrium dialysis was used to evaluate plasma protein binding of wogonin at three concentrations (0.1, 0.5 and 2 µg/mL). Results indicated a very high protein binding degree (over 90%), reducing substantially the free fraction of the compound.
    Molecules 05/2014; 19(5):5538-5549. DOI:10.3390/molecules19055538 · 2.42 Impact Factor
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    ABSTRACT: Objectives The clinical application of doxorubicin (DOX) is limited by severe systemic side effects. The aim of this study was to develop a strategy that combined the liposomal DOX (LipDOX) and intratumoral injection to reduce the toxicity and enhance the antitumor efficiency.Methods The pharmacokinetics, tissue distribution and pharmacodynamics of LipDOX compared with free DOX were investigated by intratumoral injection in murine H22 hepatoma-bearing mice at a dose of 20 mg/kg body weight. A sensitive HPLC-tandem mass spectrometry method was used to determine the DOX levels in plasma and tissues. The tumour volume and body weight of mice were measured every 3 days.Key findingsLipDOX administration resulted in 1.3-fold longer mean residence time (MRT) and 2.4-fold higher area under concentration (AUC)-time curve compared with free DOX administration in tumour. Free DOX caused higher peak plasma concentration (Cmax) than LipDOX in plasma and major organs, which may result in significant mortality for acute cardiac toxicity. After successive 21 days treatment, the final volume of tumour treated by normal saline, free DOX and LipDOX was 5.0-, 1.3-fold higher and 1.6-fold lower than the initial tumour volume, respectively.Conclusions Our results indicated that the intratumoral injection of LipDOX is a promising approach with higher therapeutic efficacy and lower systemic toxicity than free DOX.
    05/2014; 66(9). DOI:10.1111/jphp.12257
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    ABSTRACT: The compound series of traditional anticholinergics [atropine (Atr), anisodamine (Ani), anisodine (AT3), and scopolamine (Sco)], naturally occurring belladonna alkaloid, have been approved for numerous therapeutic uses since 1970s. Tiotropium, a novel M receptor antagonist for the treatment of chronic obstructive pulmonary disease, was structurally modified based on atropine-like drugs. Clinical phenomena suggested that the changes of substituent group were related to the pharmacokinetic and pharmacodynamic characteristics of the agents. In an attempt to compare the pharmacokinetics of the series of anticholinergics and investigate the subsets motivating selective anticholinergic potencies, a sensitive LC-MS/MS method was established to analyze the differences of pharmacokinetic parameters. In this paper, we determined the pharmacokinetics of atropine, anisodamine, anisodine, scopolamine, and tiotropium after i.v. and i.g. single dose administration. After i.v. administration, the maximum drug plasma concentrations (C max) of Atr, Ani, AT3, and Sco were 274.25 ± 53.66, 267.50 ± 33.16, 340.50 ± 44.52, and 483.75 ± 78.13 ng/mL. Tiotropium had a slightly higher area under the curve with a significant increase of C max value. Because of their partial solubility, Atr, Ani, AT3, and Sco had different bioavailability in rats of 21.62, 10.78, 80.45 and 2.52 %, respectively. Following i.g. administration of tiotropium, the C max value below 20 ng/mL revealed the very low oral absorption. The urinary excretion rates of Atr, Ani, AT3, Sco and tiotropium were 11.33, 54.86, 32.67, 8.69 and 73.91 %. This work provided relatively comprehensive preclinical data on the series of anticholinergics, which may be used to explain the clinical adverse effects and applications.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2014; 40(3). DOI:10.1007/s13318-014-0192-y · 1.56 Impact Factor
  • Bing Yang · Ning Li · Yang Lu · Zhixia Qiu · Di Zhao · Pengfei Song · Xijing Chen ·
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    ABSTRACT: Abstract 1. The aim of this study was to investigate the pharmacokinetics of thiamphenicol glycinate (TG) and thiamphenicol (TAP) after intravenous (i.v.) infusion of TG hydrochloride in healthy Chinese by evaluating the pharmacokinetic parameters, to provide clinical guidance in TG application. 2. In this double-blinded, phase I clinical trial, 24 healthy Chinese volunteers were recruited and divided into three groups which received a single dose of 500, 1000 or 1500 mg TG hydrochloride. Subjects in 500 mg group received further administrations at the same dose every 12 h for 5 days. The pharmacokinetic parameters were fitted on the basis of bi-phasic or tri-phasic plasma concentration-time profiles of TG and TAP. 3. Following a single dose of 500, 1000, 1500 mg TG hydrochloride, the AUC0-∞ of TG and TAP was 849.1 ± 100.3, 1305.2 ± 301.8, 2315.9 ± 546.9 and 4509.0 ± 565.9, 7506.5 ± 1112.4, 12 613.3 ± 2779.8 µgmL(-1 )min, respectively. The total clearance of TG was calculated as 0.58 ± 0.07, 0.41 ± 0.10 and 0.68 ± 0.18 L min(-1). The transformed rate constant from TG to TAP was fitted as 0.153, 0.113 and 0.118 min(-1), respectively. TAP was mainly excreted as unchanged form with no tendency of accumulation via kidney (71.9 ± 19.4%) with the renal clearance estimated at 0.097 L min(-1). 4. The established modeling was applied successfully to evaluate the pharmacokinetics of TG and TAP, providing meaningful guidance in TG clinical application.
    Xenobiotica 03/2014; 44(9). DOI:10.3109/00498254.2014.897010 · 2.20 Impact Factor
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    ABSTRACT: Abstract 1. DN604 is a new platinum agent with encouraging anticancer activity. The present study was to explore the pharmacokinetic profiles, distribution and excretion of platinum in Sprague-Dawley rats after intravenous administration of DN604. A sensitive and selective inductively coupled plasma mass spectrometry (ICP-MS) method was established for determination of platinum in biological specimens. The pharmacokinetic parameters were calculated by a non-compartmental method. 2. The area under concentration-time curve AUC0-t and AUC0-∞ for platinum originating from DN604 at 10 mg/kg were 25.15 ± 1.29 and 28.72 ± 1.04 μg/hml, respectively. The mean residence time MRT was 36.59 ± 6.65 h. The volume of distribution Vz was 11.42 ± 2.49 l/kg and clearance CL was 0.18 ± 0.01 l/h/kg. In addition, the elimination half-life T1/2z was 44.83 ± 9.75 h. After intravenous administration of DN604, platinum was extensively distributed in most of tested tissues except brain. The majority of platinum excreted via urine, and its accumulative excretion ratio during the period of 120 h was 63.5% ± 7.7% for urine, but only 0.69% ± 0.11% for feces. 3. The satisfactory half-life, wide distribution and high excretion made this novel platinum agent worthy of further research and development.
    Xenobiotica 02/2014; 44(8). DOI:10.3109/00498254.2014.889333 · 2.20 Impact Factor
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    ABSTRACT: Docetaxel (DTX) is a widely used anticancer drug for various solid tumors. However, its poor solubility in water and lack of specification are two limitations for clinical use. The aim of the study was to develop a thermosensitive chitosan/β-glycerophosphate (C/GP) hydrogel loaded with DTX for intratumoral delivery. The in vitro release profiles, in vivo antitumor efficacy, pharmacokinetics, and biodistribution of DTX-loaded C/GP hydrogel (DTX-C/GP) were evaluated. The results of in vitro release study demonstrated that DTX-C/GP had the property of controlled delivery for a reasonable time span of 3 weeks and the release period was substantially affected by initial DTX strength. The antitumor efficacy of DTX-C/GP was observed at 20 mg/kg in H22 tumor-bearing mice. It was found that the tumor volume was definitely minimized by intratumoral injection of DTX-C/GP. Compared with saline group, the tumor inhibition rate of blank gel, intravenous DTX solution, intratumoral DTX solution, and DTX-C/GP was 2.3%, 29.8%, 41.9%, and 58.1%, respectively. Further, the in vivo pharmacokinetic characteristics of DTX-C/GP correlated well with the in vitro release. DTX-C/GP significantly prolonged the DTX retention and maintained a high DTX concentration in tumor. The amount of DTX distributed to the normal tissues was minimized so that the toxicity was effectively reduced. In conclusion, DTX-C/GP demonstrated controlled release and significant efficacy and exhibited potential for further clinical development.
    AAPS PharmSciTech 01/2014; 15(2). DOI:10.1208/s12249-014-0077-z · 1.64 Impact Factor
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    ABSTRACT: Abstract 1. Triacontanol was confirmed to have a potential anti-cancer effect, the aim was to assess whether the co-administration of triacontanol alters the exposure of docetaxel via inducing hepatic CYP3A1/2 activity. The concentration of docetaxel in rats pretreated with triacontanol for seven successive days was determined, and the expression levels of CYP3A protein and mRNA were analyzed by the western blot and real time polymerase chain reaction (RT-PCR) technique, respectively. 2. The concentrations of docetaxel in rats pretreated with triacontanol were decreased, with 61.5%, 61.9% decrease in AUC0-24h and 65.7%, 54.9% reduction in Cmax (120 and 180 mg kg(-1), respectively) compared with the control. Hepatic clearance of docetaxel was enhanced in vitro and in vivo at dosage of 120 and 180 mg kg(-1), and CYP3A activity was up-regulated by measuring the formation rate of 1-hydroxymidazolam. Triacontanol preferentially induced protein expression level of CYP3A2 in a dose-dependent manner and of CYP 3A1 at dosage of 120 and 180 mg kg(-1). The mRNA expression of CYP3A1 was moderately different with the western blot results, but the trends appeared similar. CYP3A2 mRNA level was not markedly affected by triacontanol. 3. The significant triacontanol-docetaxel interaction was largely due to the induction of CYP3A1/2, which brought useful information in the clinical therapy when the combination is administered in human.
    Xenobiotica 12/2013; 44(7). DOI:10.3109/00498254.2013.870364 · 2.20 Impact Factor