Recent advances in clinical microdialysis

Clinical microdialysis (MD) is a minimally invasive sampling technique that offers selective in-vivo measurement of free, active drug or biomolecule concentrations in human tissues and organs. From a regulatory perspective, MD can thus be seen as a suitable scientific tool that meets regulatory requirements for the study of tissue distribution or bioequivalence during drug development. From a clinical perspective, the use of MD in different applications has shown the potential to rationalize drug-dosing regimens and to influence clinical decision-making, although validation and correlation of MD-derived results with clinical response are required to promote routine clinical use of the technique. From an analytical perspective, highly sensitive analytical systems have increasingly become available for MD-sample analysis, and these have further improved the quality and the power of MD-derived information. Given the constant development in recent years, MD data might become an important part of new drug submissions and clinical treatment algorithms, and might positively influence patient benefit in the future.     

Determination of tectoridin in rat plasma by high‐performance liquid chromatography and its application to pharmacokinetic studies

A simple, specific and sensitive HPLC method with UV detection was developed and validated for the determination of tectoridin in rat plasma for the first time. Chromatographic separation was performed on a Welchrom^TM C₁₈ column (150 × 4.6 mm, i.d., 5 µm) at a flow rate of 1.0 mL min^?1, using a mixture of methanol–2% HAc aqueous solution (31:69, v/v) as the mobile phase with UV detection at 266 nm. The calibration curves for tectoridin were linear over the concentration range of 1.10–274.40 µg mL^?1 in rat plasma. The intra‐ and inter‐day accuracies (RE) were within ?3.23% and 4.11%. The intra‐ and inter‐day precisions (RSD) were not more than 2.74 and 4.72%, respectively. The present method was successfully applied to the pharmacokinetic studies of tectoridin in rats after intravenous administration of three different doses. Copyright © 2009 John Wiley & Sons, Ltd.     

去甲万古霉素群体药代动力学与药效学优化研究

目的研究去甲万古霉素群体药代动力学指标差异,对患者进行药效学优化。方法选取2015年1月至2015年12月268例感染患者,将其按照年龄分为中青年组和老年组,每组各134例,采用群体药代动力学和药效学优化公式进行计算,分析患者上述指标差异。结果青年组与老年组的群体药代动力学各项指标差异明显具有统计学意义(P0.05)。结论感染患者通过去甲万古霉素药物治疗疗效确切,对革兰阳性菌的杀灭作用明显,采用群体药代动力学和药效学研究后发现,AUC24/MIC能够作为去甲万古霉素的应用指标,并以此指导临床用药效果显著,值得临床应用推广。     

HPLC method for determination of moxifloxacin in plasma and its application in pharmacokinetic analysis

Moxifloxacin is a representative of the fourth generation of fluoroquinolones. It possesses bacteriostatic activity against Gram-positive and Gram-negative bacteria. A simple and fast high performance liquid chromatography-ultraviolet detection (HPLC-UV) method was developed for moxifloxacin analysis. The separation was performed on C18 column. The mobile phase was a mixture of acetonitrile and 0.4% triethylamine solution. The regression curve was linear over the range 0.2–10.0?µg/mL. The validation parameters obey the European Medicine Agency limits. The in vivo study confirmed the practical application of the method.     

Rasagiline-encapsulated chitosan-coated PLGA nanoparticles targeted to the brain in the treatment of parkinson's disease

The aim of this study was to investigate the brain targeting potential of rasagiline-encapsulated chitosan-coated PLGA nanoparticles (RSG-CS-PLGA-NPs) delivered intranasally into the brain. Chitosan-coated PLGA nanoparticles (RSG-CS-PLGA-NPs) were developed through double emulsification-solvent evaporation technique. RSG-CS-PLGA-NPs were characterized for particle size, zeta potential, size distribution, encapsulation efficiency, and in vitro drug release. The mean particle size, polydispersity index, and encapsulation efficiency were found to be 122.38?±?3.64, 0.212?±?0.009, and 75.83?±?3.76, respectively. High-performance liquid chromatography–mass spectroscopy and mass spectroscopy study showed a significantly high mucoadhesive potential of RSG-CS-PLGA-NPs and least for conventional and homogenized nanoformulation. Pharmacokinetic results of RSG-CS-PLGA-NPs in Wistar rat brain and plasma showed a significantly high (**p?<?0.005) AUC_0-24 and amplified C_max over intravenous treatment group. Finally, the investigation demonstrated that intranasal delivery of mucoadhesive nanocarrier showed significant enhancement of bioavailability in brain, after administration of the RSG-CS-PLGA-NPs which could be a substantial achievement of direct nose to brain targeting in Parkinson’s disease therapy and related brain disorders.     

Efficient and selective analytical method for the quantification of a β-adrenoceptor agonist,isoproterenol, by LC–MS/MS and its application to pharmacokinetics studies

Isoproterenol (ISO) is a synthetic catecholamine with a powerful cardiac stimulate, bronchial smooth and skeletal muscle relaxation, coronary artery and peripheral vasodilator effects. In this study, a simple, rapid, and selective liquid chromatography–tandem mass spectrometry has been developed for the determination of ISO in rat plasma. Proteins were precipitated in plasma samples with 0.1?g?mL^?1 trichloroacetic acid and the ISO/internal standard (IS) were separated on a C₈ column. The ISO was detected by a triple-quadrupole mass spectrometer with electrospray ionization source. The transitions of m/z 212.1?→?193.9 for ISO and m/z 285.2?→?193.2 for IS were conducted through multiple reaction monitoring mode. This method was linear over the range of 2–500?n?g?mL^?1. The intra- and inter-day assay precision were observed between 3 and 10%. The accuracy was within ±11%. Stability study results demonstrated that ISO was stable in the autosampler at 4°C for 24?hr, and for 8?hr at room temperature. Only one freeze–thaw cycle at ?80°C for 24?hr was found to be stable. The validated method was successfully applied to a pharmacokinetic study of ISO in rats following subcutaneous administration.     

Determination of azasetron hydrochloride in rabbit plasma by liquid chromatography tandem mass spectrometry and its application

A sensitive and selective liquid chromatography tandem mass spectrometry method for determination of azasetron hydrochloride in rabbit plasma was developed. After addition of doxapram hydrochloride as internal standard (IS), protein precipitation by 10% trichloroacetic acid was used as sample preparation. Chromatographic separation was achieved on a Zorbax SB-C(18) (2.1 × 50 mm, 3.5 μm) column with acetonitrile-water as mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; multiple reaction monitoring mode was used to quantification using target fragment ions m/z 349.9 → 223.5 for azasetron hydrochloride and m/z 378.9 → 291.8 for the IS. Calibration plots were linear over the range of 6-1000 ng/mL for azasetron hydrochloride in plasma. The lower limit of quantitation for azasetron hydrochloride was 6 ng/mL. The mean recovery of azasetron hydrochloride from plasma was in the range 85.6-92.7%. The RSDs of intra-day and inter-day precision were both less than 12%. This method is simple and sensitive enough to be used in pharmacokinetic research for determination of azasetron hydrochloride in rabbit plasma.     

Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the determination of the novel inhibitor of angiogenesis E-3810 in human plasma and its application in a clinical pharmacokinetic study

E-3810, 6-[[7-[(1-aminocyclopropyl)methoxy]-6-methoxy-4-quinolyl]oxy]-N-methyl-naphthalene-1-carboxamide, is a novel, potent, dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors with antiangiogenic properties, now under early clinical evaluation as an anticancer agent. To investigate its clinical pharmacokinetics, a high-performance liquid chromatography-tandem mass spectrometry method was developed and validated to measure the drug in human plasma on the basis of simple protein precipitation with methanol after addition of deuterated E-3810 as internal standard. The method requires a small volume of sample (100 μl) and is rapid and selective, allowing good resolution of peaks in 5 min. It is sensitive, precise, and accurate, with overall precision, expressed as CV%, always ≤7.1%, accuracy in the range 92.7%-104.4%, and high recovery, close to 100%. The limit of detection is 0.01 ng/ml, and the lower limit of quantitation is 2.0 ng/ml. The assay was validated in the range from the lower limit of quantitation up to 500.0 ng/ml. This is the first method developed and validated for analyzing E-3810 in human plasma. The method has been successfully applied to study E-3810 pharmacokinetics in cancer patients with solid tumors who are receiving daily oral doses of the drug during the phase I trial.     

In vivo solid-phase microextraction for single rodent pharmacokinetics studies of carbamazepine and carbamazepine-10,11-epoxide in mice

The use of solid-phase microextraction (SPME) for in vivo sampling of drugs and metabolites in the bloodstream of freely moving animals eliminates the need for blood withdrawal in order to generate pharmacokinetics (PK) profiles in support of pharmaceutical drug discovery studies. In this study, SPME was applied for in vivo sampling in mice for the first time and enables the use of a single animal to construct the entire PK profile. In vivo SPME sampling procedure used commercial prototype single-use in vivo SPME probes with a biocompatible extractive coating and a polyurethane sampling interface designed to facilitate repeated sampling from the same animal. Pre-equilibrium in vivo SPME sampling, kinetic on-fibre standardization calibration and liquid chromatography–tandem mass spectrometry analysis (LC–MS/MS) were used to determine unbound and total circulating concentrations of carbamazepine (CBZ) and its active metabolite carbamazepine-10,11-epoxide (CBZEP) in mice (n = 7) after 2 mg/kg intravenous dosing. The method was linear in the range of 1–2000 ng/mL CBZ in whole blood with acceptable accuracy (93–97%) and precision (<17% RSD). The single dose PK results obtained using in vivo SPME sampling compare well to results obtained by serial automated blood sampling as well as by the more conventional method of terminal blood collection from multiple animals/time point. In vivo SPME offers the advantages of serial and repeated sampling from the same animal, speed, improved sample clean-up, decreased animal use and the ability to obtain both free and total drug concentrations from the same experiment.