Quantitation of bivalirudin,a novel anticoagulant peptide,in human plasma by LC-MS/MS:Method development,validation and application to pharmacokinetics

A rapid and sensitive method based on liquid chromatographtandem mass spectrometry （LC-MS/MS） for the determination of a novel anticoagulant peptide bivalirudin in human plasma has been developed and validated. Plasma samples were precipitated protein with acetonitrile and reextracted with dichloromethane, after which the analyte and triptorelin as an internal standard （IS） were separated on a 300SB-Cl8 column （150 mm x 4.6 mm i.d., 5 gm particle size） using 0.1% formic acid：methanol （45：55, v/v） as mobile phase. The triple-quadrupole mass spectrometer, equipped with electrospray ionization （ESI） interface, was operated in the positive ion mode, and the multiplereaction monitoring （MRM） transitions of bivalirudin and IS were at m/z 1091.0-650.4 and m/z656.5 - 249.3, respectively. The lower limit of quantification （LLOQ） was 1 ng/mL for 100 ng/mL plasma sample and the assay was linear over the concentration range 1 1000 ng/mL. The accuracy was within a range from -0.4% to 0.5% in terms of relative error （RE） and the intra- and inter-day precisions in terms of relative standard deviation （RSD） were 〈2.92 and 〈 3.36, respectively. The method was successfully applied to a pharmacokinetic study involving intravenous administration of bivalirudin （0.5 mg/kg） to Chinese volunteers.

Influence of genetic polymorphisms in drug metabolism enzymes and transporters on pharmacokinetics of different fluvastatin formulations

OBJECTIVE The purpose of the present study was to investigate the impact of fluvas.tatin formulation on the pharmacokinetics-genetic polymorphis relationship.METHODS We compared the difference between the pharmacokinetics of fluvastatin as an extended-release(ER) 80 mg tablet and an immediate-release(IR) 40 mg capsule in terms of drug metabolism enzyme and transporter ge.netic polymorphisms.In this open-label,randomized,two-period,two-treatment,crossover study,ef.fects of BCRP,SLCO1B1,MDR1,CYP2C9,and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed in 24 healthy individuals.Each treatment duration was 7 days with a washout period of 7 days between the crossover.Serum concentration of fluvastatin was evaluated using highperformance liquid chromatography-tandem mass spectrometry.RESULTS The SLCO1 B1 T521 C genotype had no statistically significant effect on IR 40 mg capsule of fluvastatinafter single or repeated doses.However,for the ER 80 mg tablet,the SLCO1 B1 T521 C genotype correlated with the AUC_(0-24) of repeat doses(P=0.01).The CYP2C9*3 genotype correlated with the AUC_(0-24) after the first dose IR40 mg capsule(P<0.05);however,the difference between CYP2C9*1/*1 and CYP2 C9*1/*3 was not statistically significant after repeated doses.CONCLUSION The effect of SLCO1B1T521C on fluvas.tatin exposure was observed and was more profound in ER and repeated dose administration than in IR and single dose administration.We recommend that formulation should be incorporated into future pharmacogenomics studies and clinical implication guidelines.

Factors underlying the association of body mass index with serum ALT in Chinese hypertensive adults without known hepatic diseases

Objective:High body mass index (BMI) is considered as the most important risk factor for elevated serum alanine aminotransferase (ALT) concentration. This study examined an array of factors, including waist circumference (WC) and folate deficiency, which may mediate the association of BMI with serum ALT concentration in Chinese hypertensive adults without known hepatic diseases. Methods:A multicenter, cross-sectional study was carried out. A total of 378 patients with mild or moderate hypertension and without known hepatic diseases were recruited from five hospitals in Harbin, Shanghai, Beijing, Xi'an, and Nanjing. Results:Of the 360 hypertensive patients with complete data in our final analysis, 13.6% had high ALT concentrations (>40 IU/L). Factors including BMI, WC, triglyceride level, and folate concentration were associated with ALT concentration in univariate analysis. Consistently higher prevalence rates of elevated ALT were observed in subjects with lower folate concentrations (≥12 vs. <12 nmol/L, 9.9% vs. 17.8%, P=0.03), with higher BMI (≥28 vs. <28 kg/m2, 21.5% vs. 11.4%, P=0.02) or higher WC (≥90 vs. <90 cm, 18.5% vs. 10.0%, P=0.02). However, in multivariate analysis, the association between BMI and ALT concentration disappeared (P=0.802 in males and 0.369 in females), while WC in females (P<0.001) and folate concentration (P=0.036 in males and 0.044 in females) remained as significant predictors for ALT concentration. Conclusions:This multicenter study demonstrated that WC and low folate concentration were important factors underlying the association between BMI and ALT concentrations in Chinese hypertensive adults without known hepatic diseases.

Peking University Health Science Center Model of Clinica Pharmacy Education and Clinical Pharmacist Services

In the 1950s, clinical pharmacy emerged in the United States and gradually developed into an indispensable component of the clinical services system, The American College of Clinical Pharmacy defines clinical pharmacy as a pharmaceutical field that focuses on the science and practice of rational drug use.

Effectiveness of hot deformation and subsequent annealing forβgrain refinement of Ti-5Al-5Mo-5V-1Cr-1Fe titanium alloy

High strength titanium alloys suffer from a limited combination of strength and ductility.Considering their micro structure,the coarseβgrain is a detrimental factor.In the present study,the effects of hot deformation and annealing treatment on theβgrain refinement of Ti-5 Al-5 Mo-5 V-1 Cr-1 Fe(TC18)titanium alloy have been investigated by using electronic backscattered diffraction(EBSD)and transmission electric microscopy(TEM).Hot compression tests of TC18 alloy were performed between 1073 and 1223 K at strain rates of 0.01 and 0.10 s^(-1)·Subsequent annealing treatments were conducted to investigate the effect of deformation microstructure on the recrystallization behavior ofβgrains.The results indicate that dynamic recovery(DRV)is the dominant restoration mechanism during hot deformation.Discontinuous dynamic recrystallization(dDRX)is significantly limited at a higher temperature in theβregion,whereas continuous dynamic recrystallization(cDRX)of theβphase is observed at a higher strain rate in the(α+β)region.The final annealing microstructure is highly dependent on the deformation microstructure.Limited dDRX during hot deformation could not effectively refine theβgrains.The refined and uniformβgrains with an average grain size of 12μm are achieved by combining hot deformation and subsequent annealing in the(α+β)region.This study provides a guide for theβgrain refinement of high strength titanium alloys.