For more than 30 years Fosfestrol (Honvan®) has been used as an estrogen for successful palliative therapy of prostatic carcinoma, but the pharmacokinetics of this compound were unknown due to the lack of analytical methods. Over the last few years we have developed a special extraction process for Fosfestrol and its metabolites from plasma with recovery yields > 90%. The simultaneous measurement of the most important compounds after intravenous and oral administration was achieved by high-performance liquid chromatography, either with the UV detector (236 nm) or with an electrochemical detector (+ 1 V). The working electrode is a carbon paste electrode constructed in this laboratory; the counter electrode is an Au and the reference electrode an Ag/AgCl electrode. The electrode processes have been clarified. Fosfestrol and its monophosphate exist only for a short time in small amounts in the circulating blood after intravenous administration, whilst after oral administration, not even traces of the phosphates could be detected in the plasma. The most important influence on plasma levels of Fosfestrol and its metabolites is due to the extraction function of the liver. Diethylstilbestrol conjugates enter into the enterohepatic circle, thus forming a possible source of DES available over more than 24 h. Only DES glucuronide and DES glucuronide-sulphate are renally eliminated and could be detected after administration over 3 days.
Chlormezanone binds to oxidized cytochrome P450 in rat liver microsomes with a binding curve according to type I like hexobarbital but less pronounced and with a general shift to the left. Ethylmorphine N-demethylation, ethoxycoumarin and ethoxyresorufin O-deethylation are inhibited by chlormezanone in mM concentrations only whereas pentoxyresorufin O-depentylation is inhibited by about 50% in microM concentrations. Luminol and lucigenin amplified chemiluminescence indicating the formation of reactive oxygen species was not influenced in concentration ranges between mM and microM, whereas NADPH/Fe stimulated lipid peroxidation showed a tendency of inhibition. But scavenger activity could not be demonstrated: the zymosan stimulated chemiluminescence of whole blood was not influenced significantly. The degradation process of chlormezanone was elucidated. The first step involves ring opening by chemical hydrolysis with subsequent formation of an unstable acylhalfaminal which is the source of 4-chlorobenzaldehyde. This aldehyde undergoes enzymatically controlled oxidation to 4-chlorobenzoic acid which is the parent compound of following phase II reactions. The second degradation product is 2-carboxyethane-sulfinic-acid-N-methylamide, which is hydrolyzed very quickly. Neither oxidation of the sulfinic acid or its N-methylamide derivative could be observed nor N-demethylation of chlormezanone.
Both chlormezanone enantiomers, for the first time obtained by enantiospecific HPLC with a 100% yield, bind to oxidized cytochrome P-450 in rat liver microsomes with a binding curve according to type I, similar to hexobarbital but less pronounced. There are no differences between the binding curves of the two enantiomers. Ethylmorphine N-demethylation, ethoxycoumarin and ethoxyresorufin O-deethylation are inhibited by both chlormezanone enantiomers at 0.1-1 mM concentrations: no differences could be found. Luminol and lucigenin amplified chemiluminescence indicating the formation of reactive oxygen species was not influenced by either enantiomer in concentration ranges between millimolar and micromolar, whereas hydrogen peroxide formation was inhibited. NADPH/Fe stimulated lipid peroxidation was not influenced. Scavenger activity could not be demonstrated: the zymosan stimulated whole blood chemiluminescence was not influenced significantly.
Der racemische Lipidsenker Ciprofibrat (1) wird nach oraler Einmalgabe überwiegend (> 90%) als Glukuronid renal und zu einem geringen Teil auch biliär ausgeschieden. Dieses aus dem Ham extrahierte Konjugat wird durch Methylieren der Carboxygruppe und Acetylieren der drei OH‐Gruppen der Glukuronsäurekomponente in das hydrophobe Methyl‐(2,3,4‐Tri‐O‐acetyl‐β‐D‐glucopyran)‐uronat übergeführt, das mil Hilfe der HPLC unter Einsatz der leicht herstellbaren Referenzsubstanz eindeutig identifiziert werden kann. Infolge der Chiralität von 1 resultieren das Glukuronid und sein hydrophobes Derivat vom Schmelzbereich 67‐78°C als Diastereomerengemisch. Das letztere konnte analytisch an einer Cyclobond I‐Säule in die beiden Diastereomeren getrennt werden.
According to earlier investigations 2-(4-(2,2-dichlorocyclopropyl)-phenoxy)-propane (4) ought to be a metabolite of the hypolipidemic agent ciprofibrate (1). However, 4 could not be detected in plasma or in urine after administration of a dose of 2100 mg 1 during the course of a multiple-dose-study. Therefore, the compound described in literature must be an unknown one and the existence of 4 as a metabolite of 1 is excluded.
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