Isolierung und Pharmakokinetik des Proazulens Matricin aus Matricaria recutita L.

Matricin ist ein lange bekanntes antiphlogistisch wirkendes Proazulen der Kamille. Weil Matricin eine labile Substanz - besonders im sauren Milieu – eine mögliche Vorstufe für den selektiven COX-2-Inhibitor Chamazulencarbonsäure nach oraler Gabe ist, war es Ziel dieser Arbeit zu untersuchen, ob Cha...

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Bibliographische Detailangaben
1. Verfasser: Ramadan, Mai
Beteiligte: Imming, Peter (Dr. Prof.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Deutsch
Veröffentlicht: Philipps-Universität Marburg 2005
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Matricin is one of the oldest known antiphlogistic proazulenes from Matricaria recutita L. Due to its chemical lability, esp. in acidic medium, matricin could be a prodrug for a selective COX-2 inhibitor, chamazulene carboxylic acid. The aim of the project was to examin, if chamazulene carboxylic acid is, after oral administration of matricin, bioavailable and if it plays a role in the matricin effects. Whereas the first aim was successfully proved, the second one could be probably approached. Lots of matricin was isolated from chamomille flowers. According to stahl method, extraction was established and the isolation critical steps were optimised. The produced crystallisation was easier and 2.0 g pure white matricin cristalls were purified. Determination of chamazulene carboxylic acid in plasma has been accomplished by developing and validating an HPLC assay. The technique is based on a single extraction of the substance from acidified 100 µl plasma with diisopropyl ether using ibuprofen as internal standard. The calibration curves were linear over the concentration range of 0.1-30 µg/ml. The intra day and inter day precision and accuracy were examined. The limit of quantitation was 0.1 µg/ml. An amount of 500 mg matricin and 300 mg of chamazulene carboxylic acid prodrug in the form of pivaloyl-oxymethyl ester were administered orally by healthy human volunteers. Afterwards, blood samples were collected. The following prostaglandins were determined simultaneously after the adminstration of both substances in urine: PGE2, PGM and 11-dehydro-thromboxan B2. Chamazulene carboxylic acid was detected in the plasma after the administration of matricin. Peak plasma concentrations of 1.3-2.2 µg/ml were observed after 75-90 minutes. The apparent volume of distribution of chamazulene carboxylic acid was larger and the elimination was slower than those of ibuprofen. After 1 h of the oral administration, ester derivative chamazulene carboxylic acid was detected. A peak plasma concentration of 1.7 µg/ml was observed after 2.5 hours. After 5 h, a second peak plasma concentration of 2.4 µg/ml was noticed followed by a slow elimination of chamazulene carboxylic acid. A third peak plasma concentration of 2.9 µg/ml was observed 25 h after the administration. Pivaloyl-oxymethyl ester of chamazulene carboxylic acid could not be detected in the plasma samples. The third peak might could be explained by the enterohepatic cycling of chamazulene carboxylic acid and/or binding to fat tissue. The effects on the arachidonic acid cascade were not significant. Only renal excretion rate of PG-M was reduced to 40% after the oral administration of matricin, which demonstrats a systemic inhibition of prostaglandin synthesis. No effects could be detected after the oral administration of the ester. Chamazulene carboxylic acid was isolated from Stevia serrata Cav. Utilizing NMR, the enantiomeric purity was determined. It has R configuration in contrast to chamazulene carboxylic acid from chamomille and yarrow. Neu azulene derivatives were synthesised. An important azulene aldehyde, chamaviolin was synthesised from chamazulene. Chamaviolin is a constituent of chamomille.