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Effects of PAMAM Dendrimers on Ocular Pharmacokinetics of Puerarin

Author: YaoChen
Tutor: SunKaoXiang
School: Yantai University
Course: Medicinal Chemistry
Keywords: Microdialysis Dendrimers Polyamidoamine PAMAM Puerarin LC-MS/MS Ocular pharmacokinetics
CLC: R285
Type: Master's thesis
Year: 2011
Downloads: 20
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Abstract

PAMAM（Polyamidoamine） is a new type of hyper-branched and three dimension- al macromolecule which possesses properties of monodispersion,non-immunogenicity, low cytotoxicity and biodegradation. As drug carrier, PAMAM can increase the skin permeability parameters, prolong the residence time in cornea and increase the bioav- ailability of the drug, and the previous study of research team indicated that PAMAM can increase the isolated corneal permeability of puerarin. It might be a potential and novel drug carrier.Microdialysis is a kind of technology sampling in-vivo to determinate the endoge- nous and exogenous substances, which is based on the dialysis principal. And it has the great advantages, such as, the little damage of tissue; makes the determination of drug concentration in the same animal simultaneously be possible; controls itself, decreases the residual and the number of animal; continuous real-time monitoring of drug in tissues. And it has been widely applied in pharmacokinetics.We chose the PUE as the model drug, and established the microdialysis model to investigate the effect of different generation PAMAM on the pharmacokinetics of PUE by LC-MS/MS. It will provide the evidences for the application of PAMAM as the ocular carrier.The ocular humor aqueous microdialysis model and LC-MS/MS method were established, determined the in-vivo/vitro recovery of probes. We chose the MAB/3 probe to establish the microdialysis model, and the recovery in-vivo and in-vitro was （16.25±1.13）%、（30.16±0.49）%, respectively. The LC-MS/MS conditions were: TSQ Quantum Access tandem mass spectrometer （Thermo Electron Corporation, USA） with electrospray ionization （ESI） source operated in negative ionization mode.. The analytical column C18 （Phenomenex Luna, 150mm×2.1 mm i.d., 5μm） was used. The mobile phase was a mixture of acetonitrile/water （40:60, v/v） with ammonium acetate in concentration of 0.2m mmol·L^-1. Flow rate was 0.2 ml·min^-1; run time was 5 min.The mass spectrometer was operated under selective reactions monitoring （SRM） mode. The spray voltage was 3 kV. Sheath gas and auxiliary gas pressures were 30 and 5 psi, respectively. The capillary temperature was 350℃, argon gas pressure was 1.5 milli-torr. The collision induced dissociation voltage was 25 eV for puerarin and astilbin （IS）. The transitions （precursor to product） monitored were m/z 415.0→295.0 for puerarin, 449.1→285.0 for IS. Data acquisition and processing were accomplished using the Xcalibur version 1.4.1 software. The assay was reproducible and linear for puerarin in dialysis sample in the range of 2¹000 ng·mL^-1.The lower limit of quantification （LLOQ） of the analytes was 2 ng·mL^-1. The intra-day and inter-day precision of analysis （RSD） was all lower than 10% for each analyte at concentrations of 2,5,1000 ng·mL^-1, and the extraction percentage of this method was 79%⁸6%.The accuracy, precision, sensitivity, specificity and linearity of this method satisfied the requirements of pharmaceutical analysis in biological samples.In our study, we investigated the pharmacokinetics of puerarin（1%, w/v）and the mixtures of 0.2%（w/v） PAMAM（G3.0, G4.0, G5.0） and puerarin. And the AUC0-t value of puerarin with 0.2% （w/v） PAMAM （G3.0,G4.0,G5.0） were 2.3-, 3.5- and 2.1-fold of that of the control group, and the Cmax value of puerarin solution with 0.2% （w/v） PAMAM vs the control group was 1.5-, 2.5- and 1.3-fold. The results suggested that permeability and the relatively bioavailability was increased with the increased generation of PAMAM. But, the enhancement of G5.0 PAMAM dendrimer was much lower than G3.0 and G4.0. It maybe attitude that the G5.0 PAMAM dendrimer could contain more puerarin than G3.0 and G4.0, which led to the slowly permeablity and long half-time.Overall, the ocular microdialysis suggested that the PAMAM dendrimer may increase the absorption of puerarin in different degree, and increase the bioavailability, and it depends on the generation of PAMAM dendrimers. In conclusion, the PAMAM dendrimers could become a potential ocular drug delivery system.

Effects of PAMAM Dendrimers on Ocular Pharmacokinetics of Puerarin

Abstract

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