[Biomimetic oxidation of clemastine hydrogen fumarate]. / Untersuchungen zur biomimetischen Oxidation von Clemastinhydrogenfumarat.

The reaction of clemastine fumarate (1) with the biomimetic system manganese(III)-5,10,15,20-tetrakis(pentafluoro-water. The reaction of 1 in aqueous solution with manganese(III)-5,10,15,20-tetrakis (pentafluorophenyl)-beta-tetrasulfonatoporphyrin chloride (MnTPFPS4PCl) as catalyst additional generates products of aromatic hydroxylation. Products were identified by TLC, UV, and MS. Thereby we found a close conformity with rat metabolism.

[The biomimetic oxidation of propiverine hydrochloride and 1-methyl-4-piperidylbenzilate]. / Untersuchungen zur biomimetischen Oxidation von Propiverin-hydrochlorid und 1-Methyl-4-piperidyl benzilat.

The reaction of propiverinhydrochloride (1) and 1-methyl-4-piperidyl benzilate (2) with the biomimetic system manganese(III)-5,10,15,20-tetrakis(pentafluorophenyl)porphyrin chloride (MnTPFPPCl)/pyridine/hydrogen peroxide affords unchanged 1 and 2 and 15 potential metabolites, which were isolated and identified. These compounds are products of cleavage of the ester bond, of O-dealkylation, aromatic oxidation, respectively of decarboxylation, demethylation, and N-oxidation, Products were identified by TLC, UV, and MS in comparison with authentic samples. Thereby we found a nearly conformity with rat metabolism.

[Pharmacokinetics (rats and rabbits) of N-methyl-4- piperidinylbenzilate (Po)3]. / Untersuchungen zur Pharmakokinetik (Ratte und Kaninchen) des N-Methyl-4-piperidinylbenzilats (Po).

Plasma concentrations of the anticholinergic diphenylmethane derivative N-methyl-4-piperidinylbenzilate (Po;1) in rats after i.v. and p.o. administration of the drug and in 6 rabbits after i.v. administration of the drug were estimated by a gc capillary column technique in connection with detection by thermoionisation. Furthermore, after i.v. administration of the drug its concentrations in different tissues (heart, lung, liver, kidneys and brain) were estimated in rats. The results show a fast absorption of the drug after p.o. administration and also a fast decrease of 1 plasma concentrations in all plasma concentration curves obtained indicating a fast distribution of 1 in deeper tissue compartments. A high affinity especially to the lung and the heart can be derivated from the high 1 tissue concentrations in the rat. A common feature of all 1 plasma concentration curves obtained is the repeated appearance of concentration peaks which is particularly marked in the individual 1 plasma curves at the rabbits. We observed great interindividual differences in the pharmacokinetic behaviour. Furthermore, some plasma concentrations are below the detection limit of the analytical method used. These are the reasons why curve fitting to usual pharmacokinetic compartment models and the determination of parameters i.e. AUC and MRT is not suitable. However, the results agree with the assumption of a multi-compartment model at which the drug is periodical released in the general circulation. Interactions with biological membranes resulting out of the amphiphily of the drug are some possible reasons for the outstanding pharmacokinetic behaviour.

[Clemastine metabolites in the feces and urine of the rat]. / Clemastinmetaboliten aus Kot und Harn der Ratte.

After oral application of clemastine [(1), (+)-2-(2-[1-(4-chlorophenyl)-1-phenylethoxy]-ethyl)-1-methylpyrrol idine- hydrogenfumarate], to rats (200 mg/kg) 18 phase I- and II-metabolites have been detected and isolated from urine and faeces. They are products of fission of the ether bond, of aromatic and aliphatic oxidation, respectively, of alcoholic dehydration, decarboxylation, N-oxidation, O-methylation and conjugation as phase II steps. Phenolic compounds represent-in contrast to some other diphenylmethane derivatives, especially basic benzilates (propiverine, denaverine)-the main metabolic products formed by dihydrodiol mechanism or direct oxigenation. The structure of metabolites were elucidated by MS.

[Biotransformation of denaverin (Spasmalgan) in the rat]. / Biotransformation von Denaverin (Spasmalgan) bei der Ratte.

After oral application of denaverine hydrochloride to rats (200-250 mg/kg) 12 metabolites have been detectecd in urine. Besides the unchanged drug, 8 metabolites were identified by MS as 2,2-diphenyl-(2-dimethylaminoethyl) acetate (3), diphenylacetic (5) and benzilic acid (6); methyl-and ethyl [2-(2-ethylbutoxy)-2,2-diphenyl]acetate (7, 11), methylbenzilate (10), N-demethyl-1 (12) and 3,3-diphenyl-morpholin-2-one (13). 6 and the metabonate 13 represent the main metabolic products. Compounds 7 and 11 indicate the metabolic pathway about an alkoxybenzilic acid (4). Phenols resp. conjugates were not detected.

[The biotransformation of propiverin hydrochloride (Mictonorm)]. / Zur Biotransformation von Propiverinhydrochlorid (Mictonorm) bei der Ratte.

Propiverine hydrochloride [1; hydrochloride of O-n-Propyl-(N-methylpiperidinyl-4)-benzilate; Mictonorm] is metabolized after p.o. application of 25 mg/kg on rats almost completely. Besides of small amounts of unchanged 1 in urine were detected the phase-I metabolites N-methylpiperidinyl(4)-benzilate (2), 2,2-diphenyl-5-methyl-1, 4-dioxan-3-on (3), N-oxide of 2 (4), benzilic acid (5) and O-n-propylbenzilic acid (6) using ms, dc and hplc comparison of the isolated compounds with authentic samples. The structure of further metabolites, i.e. monohydroxy-benzophenone (7), acetoxy-1-derivatives (8) and ethylbenzilate (9) were elucidated by high resolution MS.

[The stability of bromhexine and the structure of its degradation products]. / Zur Stabilität von Bromhexin und zur Struktur seiner Abbauprodukte.

Refluxed acid or neutral aqueous solutions of Bromhexine (1) show four degradation products. 1 is decomposed at room temperature (20 degrees C; 1 year) less than 1%. Degradation products of crystalline 1 are not detectable in the temperature-moisture-test. Under normal storage conditions a 5-year stability for aqueous solutions and a more than 10-year stability for crystalline 1 are estimated. Very small amounts of three degradation products were isolated by TLC. According to MS-, UV- and IR-analysis their structures are 3-cyclohexyl-6,8-dibromo-chinazoline-4-one (2a), 3-cyclohexyl-6,8-dibromo-chinazoline (2b) and 3-amino-4,6-dibromo-benzaldehyde (3). The structure of N-Methylcyclohexylamine is supposed for a further product. Ms fragmentation and degradation mechanisms are discussed.

[Analysis and stability of propiverine hydrochloride (Mictonorm)]. / Zur Analytik und Stabilität von Propiverinhydrochlorid (Mictonorm).

In acid, neutral and alkaline solution the hydrolytic degradation of the spasmolytic agent Mictonorm (1) was determined. As degradation products ester- and/or ether fragments (2-5), benzophenone (6) and a compound X (7) were identified. In comparison N-Methylpiperidinyl(4)-benzilate (2) and benzilic acid (3) were also investigated in the isothermal quick-assay test. The test showed that the ether bound in 1 was hydrolyzed before the ester group. The compounds 5-7 are formed also direct from 3.

[The evaluation of non-isothermal short-term tests of drug solutions]. / Zur Auswertung nichtisothermer Kurzzeittests von Arzneistofflösungen.

Non-isothermal short-term tests to examine the stability of drug solutions, are critically discussed with regard to their application to simple and complex reaction mechanisms. The influence of additional temperature dependences (ionic product of water, activity coefficient) is assayed. By example of the decomposition of tetracaine hydrochloride and acetylsalicylic acid, the evaluation of experimental results is discussed considering these factors.

[HPLC of trapidil (Rocornal) and metabolites (author's transl)]. / HPLC von Trapidil (Rocornal) und Metaboliten.

Trapidil (1; Rocornal) and 10 metabolites can be separated by a gradient technique on reversed phases (RP-8 instant columns) using the eluents methanol/water and acetonitrile/phosphate buffer (pH = 5.4); ultraviolet detection. Furthermore, HPLC techniques for purity testing and for determining 1 in serum are described.

[Biotransformation and Stability of Hydrocotarnine and Diazocarbonylhydrocotarnine and -hydrohydrastinine derivatives (author's transl)]. / Biotransformation und Stablilität von Hydrocotarnin und Diazocarbonylhydrocotarnin-bzw.-hydrohydrastininverbindungen.

After oral application of the weakly basic (pKs = 6.18-6.26) and relatively stable (1 at pH = 7.4; t1/2(35 degrees C) = 6.9 h) secondary 1-diazocarbonylhydrocotarnine or -hydrohydrastinine derivatives 1-4 and of hydrocotarnine (6) to rats, a total of 18 metabolites, predominantly isoquinolines of varying degrees of hydrogenation (7-19), were isolated from 48-hour urine specimens. These isoquinolines result from cleavage of the C-1/C-1' bond as well as from oxygenation (11, 15, 17-19), N-dealkylation (13, 15, 17-19) and O-dealkylation (8-12, 18, 19). Among these isoquinolines were some phenolic betaines (8-11) of which 9 is the major metabolite of the cotarnine derivatives. Furthermore, C-1-substituted metabolites as well as metabolites with benzo-1,2-diazaindolizine (23, 24) or benzodiazepine structure (20, 21) were isolated. Also in an aqueous-alkaline or an aqueous-acidic medium, the cleavage of the C-1/C-1' bond as well as the formation of benzodiazepines follows a non-enzymatic pathway as evidenced by stability studies. The structures assigned to the different compounds are supported by high-resolved mass spectra, further spectroscopic studies (UV, IR and 1H-NMR spectra) and, in part, by comparison with authentical material.

[Comparative studies on the stability of aqueous drug solutions in the isothermal and the non-isothermal short-time test as well as in the long-time test. Part 2: The stability of aqueous tetracaine solutions in the non-isothermal short-time test (author's transl)]. / Vergleichende Untersuchungen zu Stabilität wässriger Arzneistofflösungen im isothermen und nichtisothermen Kurzzeittest sowie im Langzeitversuch. Teil 2: Stabilität wässriger Tetracainiösungen im nichtisothermen Kurzzeittest.

A study of the hydrolytic degradation of tetracaine solutions at various pH values demonstrates that the results from non-isothermal stability testing with logarithmic rise in temperature are in good agreement with the activation energies determined, under analogous conditions, by means of the isothermal short-time test and long-time test. The range of the maximum of stability is more clearly evinced by the non-isothermal short-time test than by the isothermal stability test. The comparison of the two methods reveals that the deviation of the reaction rate constants is greater in the non-isothermal test, which is due to the calculation required for the logarithmic rise in temperature. The results obtained with tetracaine evidence that the non-isothermal stability test is an appropriate method for the rapid determination of stability parameters (e.g. stability maximum, hydrolysis velocities) in the frame-work of testing potential drugs for stability and in the optimization of prescriptions.