1Clinical Pharmacokinetic Study On Cephalexin, A Substrate Of Pept1

Recently, cephalexin has been often used as a probe drug for PEPT1instudies, which could reflect the activity of this transporter. Thus, changes in theplasma concentrations due to the extraneous factor effect on the transportersmay impair the clinical outcome of cephalexin therapy. Based on previousresearches, we have conducted the following studies.1) We evaluated theinfluence of different oral administration times on cephalexin pharmacokineticsin postprandial and fasting male volunteers, and determine whether thisvariation would impair the clinical outcome of cefalexin.2) We investigated theeffect of zinc sulfate on cephalexin pharmacokinetics when administeredconcurrently or at strategically spaced dosing times designed to avoid thepotential interaction.3) We compared the effects of amlodipine on thebioavailability of cephalexin and cefuroxime axetil.Besides, we conduct some preclinical reserch on felotaxel, which is underclinical development by Hengrui Pharmaceutical. Felotaxel is one of the mostpromising compounds in new class of9-β-dihydro-9,10-O-acetal taxane. In ourstudy, a LC-MS/MS method was developed and validated for the first time todetermine felotaxel levels in human plasma and urine and rats tissues, which would be helpful for its clinical pharmacokinetics study.Our study can be divided into following parts:Part1Chronokinetic Study of Cephalexin in Postprandial and FastingVolunteersAIMS The present study was to determine whether diurnal variations ofcephalexin pharmacokinetics exist in postprandial or fasting male volunteers andwhether the clinical outcome of cefalexin would be impaired by this variation.METHODS This is a study consisted of two randomized, crossover, single-dosestudy of cephalexin in healthy male subjects. Cephalexin was given orally to10subjects under the postprandial conditions or after an8-hour fast, in08:00h or20:00h. Pharmacokinetic parameters were analyzed by paired samples t test forthe presence of diurnal variation.RESULTS In postprandial experiment, after oral dose under postprandialcondition, time-dependent changes in cephalexin pharmacokinetics weresignificant. t1/2was prolonged obviously （P <0.05） and Cmaxwas lower （P <0.05） after the20:00h compared to the08:00h administration. However, infasting experiment, no significant differences were found in the mainpharmacokinetic parameters of cephalexin administered at two occasions afterfasting. Furthermore, by comparing two experiments, food intake wasdetermined to be a significant factor related to inducing daily variation in t1/2butnot in Cmaxwith the paired sample t test （P <0.05）.CONCLUSION In this study, time of administration may affect the pharmacokinetics of cephalexin under the postprandial condition. And thefasting may suppress the diurnal variations in cefalexin pharmacokinetics.Part2The Effect of Staggered Administration of Zinc Sulfate on thePharmacokinetics of Oral CephalexinAIMS To investigate the effect of zinc sulfate on cephalexin pharmacokineticswhen administered concurrently or at strategically spaced dosing times designedto avoid the potential interaction in healthy volunteers.METHODS In this study, all subjects （n=12） were randomized to receive thefollowing four treatments separated by a wash out period of7days: cephalexin500mg, alone, concomitantly with zinc250mg,3h after zinc250mg, or3hbefore zinc250mg.RESULTS All subjects completed the study safely. Zinc supplementsadministered concurrently with cefalexin significantly decreased the Cmax,AUC0-∞and the time that the plasma concentrations of the drug remain abovethe minimal inhibitory concentrations （MIC） of the pathogen organism （T>MIC） of cefalexin [mean percentage decrease of31.05%（22.09%,40.01%）,27.40%（18.33%,36.47%） and22.33%（12.51%,32.16%）, P <0.05] comparedwith administration of cefalexin alone. Also, administration of zinc3h beforecefalexin decreased the Cmax, AUC0-∞and T> MIC of the drug compared withadministration of cefalexin alone. In contrast, the pharmacokinetics of cefalexinwas not notably altered by administration of zinc3h after cefalexin dosing （P>0.05）. CONCLUSION The significant interaction between zinc and cephalexin mightaffect the clinical outcome of cephalexin therapy. The dosing recommendation isthat zinc sulfate can be safely administered3h after cephalexin dose.Part3Effects of Amlodipine on the Oral Bioavailability of Cephalexin andCefuroxime AxetilAIMS To compare the effects of amlodipine （AML） on the bioavailability ofcephalexin （LEX） and cefuroxime axetil （CXM）METHODS Twenty four healthy males were randomized into four treatmentsaccording to a crossover design with a14-day washout. After an overnight fast,subjects were administered orally LEX500mg alone, LEX500mg2h afteroral administration of AML5mg, CXM500mg alone or CXM500mg2h afteroral administration of AML5mg. Pharmacokinetic data was analyzed by anoncompartmental modeling with the WinNonlin software.RESULTS The geometric mean （GM） ratios were1.38AUC for LEX and1.27for Cmaxfor LEX following with AML versus alone. In contrast, no significantdifferences were found in the pharmacokinetic parameters of CXM betweentreatments （P <0.05）.CONCLUSION1) AML possesses an enhancement effect in β-lactamantibiotics bioavailability, in this case, LEX;2) this interaction may be specificto the peptidomimetic β-lactam antibiotics. 2LC-MS/MS method for the determination of felotaxel inrat tissues and human plasma and urineAIMS To developed a LC-MS/MS method for the determination of felotaxel inrats tissues and human plasma and urineMETHODS In this study, a rapid and sensitive analytical method based onLC-MS/MS has been developed for the determination of felotaxel in rats tissuesand human plasma and urine.RESULTS For all matrices, sample preparation involved liquid-liquidextraction with ethyl acetate was used. Calibration curves （1/x2weighted）offered satisfactory linearity （r2>0.995） within the test range. The lower limitof quantitation （LLOQ） for all matrices was5ng·ml^-1. The calibration standardcurves were reproducible for all matrices with inter-and intra-day variability inprecision and accuracy being less than15%at all quality control concentrations.Recoveries and matrix effects were satisfactory in all the biological matricesexamined.CONCLUSION The method had highly accuracy, sensitive, specificitive,selectivity. It could be used for pharmacokinetics study of felotaxel in future.