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Study on Quantitative Determination, Pharmacokinetics, Union Medication Pharmacodynamics for Fu-an-te

Author: TongXin
Tutor: YiYiMu
School: Huazhong University of Science and Technology
Course: Pharmacy
Keywords: Fu-an-te LC/MS/MS Pharmacokinetics Antitumor CYP450 isozyme
CLC: R96
Type: Master's thesis
Year: 2010
Downloads: 29
Quote: 0
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Abstract

The active content for Fu-an-te, which was ubiquitous in nature, is high effective and low toxic on treating tumor. Theoretically, the strong hydrophobic nature of it should be benefited from the preparation of the nanoliposome. This presented study aims at establishing quantitative determination in biological sample, and examining the pharmacokinetic characteristics in vivo. In addition, the union medication anti-tumor effect on certain cancer and specific site delivery effect was also examined, as well as the cytochrome P450 isozyme inhibiting effect.This presented study, with Glycyrrhetinic acid as internal standard content, and acetonitrile-water-ammonium acetate as mobile phase, established the quantitative dertemination, which was evaluated from the aspects of the recovery, the accuracy and sensitivity. This method was approved as a rapid, sensitive and reliable one, with a LLOQ of 6.86 ng/mL for a plasma sample size of 100μL, and with an analysis time of 3 mins.Based on this dertemination and with animal models such as Beagle dog, Spragure - Dawley rats and Kunming mice, the pharmacokinetic study was done under the atrioventricular model, and the plasma protein binding ratio was calculated by dialysis method. Besides, distribution in vivo, excretion and biotranformation in vivo was also been examined. LC/MS was used for examining and chemical structure speculating of possible metabolites. The AUC0→6h is positively related to the dosage, and the linear correlation coefficient r > 0.99. The plasma protein binding ratio is slightly higher than the normal level ( > 80%). In addition, a high reservation level in liver was found after a long time distribution. In contrast, gastrointestinal concentration was obviously higher than all the other tissues at the beginning of distribution and falls down rapidly along with the plasma concentration declines. The main metabolites in vivo are glucuronyl transferase content M1 and methylation glucuronyl transferase content M2 for both the active content and its nanoliposome formulation. No dependence was found between the exposure level and the formulation.With human lung tumor A-549 nude and human liver tumor BEL-7402 nude mice transplant tumor as subjects, the anti-tumor effect of Fu-an-te and adriamycin singly or combinly was compared seperatly with positive control medicine mitomycin. Both the two kinds of transplantation tumor growth were not significantly supressed by singly medication therapy. Combining with the adriamycin, the Fu-an-te significantly supressed the liver-transplantation tumor growth with a relative tumor increment rate T/C (%) of 24%. And the combination also showed a suppression effect on lung-cancer-transplantation tumor but not significant, the relative tumor increment rate T/C (%) is 62.0%.The inhibition effects of Fu-an-te towards five CYP450 isozymes in human, CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 was examined with the known CYP450 isozyme inhibitors as positive control. No significant inhibitory effect was found in the in vitro test.Therefore, The Fu-an-te is easily plasma protein combining, and the in vivo distribution seems to meet with 3 rooms model. There was a possibility for liver targeting. The Fu-an-te was mainly excreted with bile as metabolics. And the interaction between it and the other CPY450 isozyme-depending medicines is less impossible for a CPY450 isozyme inhibition effect free.

Study on Quantitative Determination, Pharmacokinetics, Union Medication Pharmacodynamics for Fu-an-te

Abstract

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