Klaus-Peter Zeller

Pharmacokinetics and Metabolism of Mitoxantrone A Review

SummaryMitoxantrone, a cytotoxic anthracenedione derivative, has given clinical evidence of beneficial activity in breast cancer, lymphoma and leukaemia. Several different mechanisms of action have been suggested to account for this. In addition to intercalation, biological effects such as electrostatic interactions with DNA, DNA-protein cross-links, lmmunosuppressive activities, inhibition of topoisomerase II, Prostaglandin biosynthesis and calcium release have been described.Various methods of drug monitoring in biological fluids and tissues are available: the highest sensitivity has been achieved with high performance liquid chromatography with electrochemical detection, radioimmunoassay and enzyme linked immunosorbent assay. Early pharmacokinetic studies of mitoxantrone in experimental animals using radioactive material showed an extensive tissue distribution and a long terminal plasma half-life.The best fit for the plasma concentration-time curve in humans is achieved in a 3-compartment model. All studies reported a short absorption half-life of between 4.1 and 10.7 minutes, with the distribution phase being between 0.3 and 3.1 hours. In contrast, the values of the terminal half-life are quite variable, ranging from 8.9 hours to 9 days. Differences might be attributed to assay sensitivity, number and weighting of data points beyond 24 hours and coadministration drugs. Many studies showed a very large volume of distribution with sequestration of mitoxantrone in a deep tissue compartment. In autopsy studies, relatively high tissue concentrations have been measured in liver, bone marrow, heart, lung, spleen and kidney.Bile is the major route for the elimination of mitoxantrone, with lesser amounts excreted in the urine. Several metabolites have been separated, 2 of which were identified as the monocarboxylic and dicarboxylic acid derivatives.Mitoxantrone is usually administered by rapid intravenous infusion at 3-weekly intervals; other regimens include continuous infusion, daily repeated doses or weekly administration. In peritoneal carcinosis, the pharmacological advantage of intraperitoneal administration is clear. The optimal regimen for different disease categories with respect to efficacy and side-effects remains to be determined in future clinical trials.

Determination of naphthodianthrones in plant extracts from Hypericum perforatum L. by liquid chromatography–electrospray mass spectrometry

The determination of the naphthodianthrone constituents in extracts of dried blossoms of Hypericum perforatum L. by combined HPLC-electrospray mass spectrometry is described. Hypericin (1), pseudohypericin (2) and their precursor compounds produce intensive negative quasi-molecular ions by deprotonation provided a non-acidic eluent system is used in the HPLC separation. From the [M-H]- ions formed in the electrospray ionization process characteristic daughter ion spectra can be obtained by collisional activation which have been studied by tandem mass spectrometry.

Untersuchungen zur Wolff-Umlagerung—II : Die wanderungsfähigkeit von wasserstoff, methyl- und arylgruppen

Abstract The migration ability of hydrogen, the methyl, phenyl, p-methoxyphenyl, and p-nitrophenyl groups in the Wolff-rearrangement has been investigated with the aroyl-acyl-diazomethanes 1a-d. The results of the thermal and photochemical (direct and sensitized) reaction are discussed. The insertion of the intermediate aroyl-acylcarbenes 2 in the OH-bond of ethanol yielding 2-ethoxy-1,3-diketones 7 competes with the rearrangement of 2 into ketenes (3 and 4) and following formation of β-ketoesters 5 and 6. With the 18O- and 13C-labelled compounds 1a′ and 1b′ it is shown that in the electron impact induced Wolff-rearrangement no graduation in the migration aptitude of H, CH3 and C6H5 exists.

The dimethyldioxirane-mediated oxidation of phenylethyne

The product pattern found for the dimethyldioxirane-mediated oxidation of phenylethyne strongly depends on the reaction conditions. Dimethyldioxirane generated in situ from caroate (HSO(5)(-)) and acetone in acetonitrile-water furnishes phenylacetic acid as the main product. With solutions of dimethyldioxirane in acetone, mandelic acid and phenylacetic acid are mainly formed. The relative abundances of the two acids depend on the residual water present in the dimethyldioxirane-acetone solution. Application of thoroughly dried solutions of the reagent effects increased formation of mandelic acid. When phenylethyne is oxidized by dimethyldioxirane transferred into tetrachloromethane, to minimize traces of water even further, oligomeric mandelic acid is obtained. The results are rationalized by the initial formation of phenyloxirene, which is known to equilibrate with phenylformylcarbene and benzoylcarbene. Subsequent Wolff rearrangement produces intermediate phenylketene, which can be trapped by water as phenylacetic acid or suffer from further oxidation to the alpha-lactone of mandelic acid. The alpha-lactone can either react with water to yield mandelic acid or, under anhydrous conditions, to yield oligomeric mandelic acid. In addition to mandelic acid and phenylacetic acid phenylglyoxylic acid, benzoic acid and benzaldehyde are observed as reaction products. The formation of phenylglyoxylic acid by transfer of two oxygen atoms to the unrearranged carbon skeleton of phenylethyne followed by oxygen insertion into the aldehydic C-H bond of the intermediately formed phenylglyoxal is discussed. In a second pathway this acid is formed by partial oxidation of mandelic acid. Benzaldehyde and benzoic acid are explained as products of the oxidative degradation of the alpha-lactone by dimethyldioxirane. Under in situ conditions benzoic acid is also formed by caroate initiated oxidative decarboxylation of phenylglyoxylic acid and/or intermediate phenylglyoxal.

Zur photolyse von 1,2,3-thiadiazolen—II : ESR-studien zur stickstoff-eliminierung

Abstract The photochemically induced elimination of nitrogen from 1,2,3-thiadiazoles (I) is investigated by ESR spectroscopy. Crystalline probes and probes embedded in a matrix are irradiated at −170° in the ESR cavity. The observed signals show the sulphur pattern and indicate a radical mechanism for the nitrogen elimination.

Photolyse von 2-oxo-[2-13c]-1-diazocyclohexan. Ein beitrag zum oxiren-problem

Zusammenfassung Ausgehend von K13CN wird die Synthese von 2 - Oxo - [2 - 13C] - 1 - diazocyclohexan (10) beschrieben. Die Photolyse von 10 in Dioxan/Wasser ergibt eine Cyclopentancarbonsaure, die laut 13C - NMR - Spektrum und massenspektrometrischer Fragmentierung die gesamte Markierung am Carboxykohlenstoff tragt. Eine intermediare Oxirenbildung wird dadurch ausgeschlossen.

A New Eudesmane Type Sesquiterpene from Inula Viscosa

Investigation of Inula viscosa of Jordanian origin afforded the new sesquiterpene 1 g -hydroxyilicic acid in addition to the known 2 g -hydroxyilicic acid.

Generation of formaldehyde by N-demethylation of antipyrine: Detection of formaldehyde in bile by 13C-NMR spectroscopy

The importance of NMR spectroscopy as a tool to investigate metabolic events in vitro and in vivo becomes more and more evident. Particularly 13C-NMR spectroscopy is able to deliver a wide range of information regarding the chemistry of xenobiotics in vivo. We studied the N-demethylation of N-methyl-13C-labelled antipyrine using an isolated perfused rat liver with a fluorocarbon suspension (FC 43) as oxygen carrier. Bile was collected in different fractions during the experiment. On the vascular side metabolite formation was monitored by continuous flow NMR spectroscopy. In bile the metabolic events were detected by standard NMR techniques. The bile spectra exhibit, among others, a signal at 84.2 ppm, indicating formaldehyde hydrate derived from the N-methyl group of antipyrine by an oxidative metabolic pathway. Neither formaldehyde hydrate nor other oxidation products could be detected in the vascular perfusate. The biliary excretion of considerable amounts of formaldehyde during the N-demethylation of antipyrine might have toxicological consequences for the intra- and extrahepatic bile ducts.

Synthesis and structural elucidation of biliary excreted thioether derivatives of mitoxantrone

1. Hplc-MS coupling has been used for the identification of thioether derivatives of the anticancer agent mitoxantrone in the bile of pig. 2. Three biologically relevant new thioether derivatives of mitoxantrone have been synthesized by a horseradish peroxidase-catalysed reaction. 3. The thioether derivatives have been characterized by means of ion-spray tandem mass spectrometry and nmr spectrometry including two-dimensional techniques. 4. The carbon-sulphur bond formation takes place at the hydroquinone moiety of the anthraquinone skeleton pointing to the importance of a tautomeric equilibrium between different species of the oxidized drug. 5. The occurrence of the synthesized compounds in biological systems suggests a metabolic pathway that may be relevant for the cytotoxicity of mitoxantrone (oxidative activation).

13C13C spin spin coupling constants in azulenes

[4-13C]- Azulene and [4-13C]-4-methylazulene have been synthesized. The 13C13C spin coupling constants have been measured and interpreted in terms of πMO theory.