Pharmacokinetic profile of metaclazepam (Talis), a new 1.4-benzodiazepine. Influence of different dosage regimens on the pharmacokinetic profile of metaclazepam and its main metabolite under steady-state conditions.

The pharmacokinetic parameters of the new 1.4-benzodiazepine metaclazepam (Talis) were investigated. In particular, the question of whether the drug and/or its main metabolite accumulates in the body under steady-state conditions was studied. Two dosage regimens were compared by a randomized two-way crossover design: a once-a-day dosing (15 mg metaclazepam in the evening, = A) versus a twice-a-day dosing (5 mg in the morning plus 10 mg in the evening, = B) over ten days in twelve healthy male volunteers. Plasma levels of metaclazepam and its major biotransformation product, N-desmethylmetaclazepam, were determined. Comparing the treatments, significant differences were found for Cmax, but not for AUC-3 and Tmax. These results are also valid for the comparison of days 1 and 10 of each treatment. Higher Cmax values for dosage regimen A were found but Tmax and Cl/F remained stable in both treatments taking into account that 12 hours after the first medication, another dosing took place in treatment B. Eight hours after application, plasma levels were markedly low, Cmax values after single-dosing were nearly twice as high as after multiple dosing. Therefore based on these pharmacokinetic findings, a second dosing seems to be necessary; the clinical relevance needs further investigation. It has been reported, in fact, that it is in general very difficult to demonstrate a correlation between blood levels and therapeutic effects for 1.4-benzodiazepines (1,2).

[Mass spectrometric data on some drugs, their biotransformation products and intermediate products of illegal synthesized narcotics]. / Die massenspektrometrischen Kenndaten einiger Arzneistoffe, deren Biotransformationsprodukte sowie der Zwischenprodukte illegaler Rauschgiftsynthesen.

Additional mass spectral data of some rather unusual drugs and their biotransformation-products are presented updating the three large and authoritative mass spectra data collections for forensic/clinical toxicological purposes published by Finkle, Foltz and Saferstein et al. Furthermore mass-spectra data of chemicals, intermediates, by-products and final products of illegal drug syntheses are summarized in one chapter.

[Contribution to biotransformation and analysis of the psychopharmacon mefexamide (author's transl)]. / Beitrag zu Biotransformation und analytik des Psychopharmacons Mefexamid.

After oral administration of a therapeutic dosage (400 mg) Mefexamide (I), six excretion products were detected in human urine and subsequently identified by GC/MS and TLC: in addition to the unchanged drug (I) in the acidic extracted urine without hydrolysis p-methoxiphenoxiaceticacid-methylester (II) and p-methoxiphenoxiaceticacid (III) were detected; the latter two and p-hydroxyanisole (IV) were also found in the acidic extract after hydrolysis (with hydrochloric acid or enzymatic). In the alkaline urine extract besides the unchanged drug (I) and the main metabolite V (partially described previously by Forist et al. [8]1), metabolite VI, which occurred only in very small amounts, could be detected. Additionally, 2-diethylaminoethylamine (VII) was identified as an artifact in the alkaline extract after acidic hydrolysis. Hydrolysis of mefexamide with hydrochloric acid led to substances II, III, IV, and VII. For the main metabolite V, a synthesis route is described. Approximately 15% of the administered drug was recovered in the 24-h urine; substances I and V could be detected a least 72h after application.

Determination of the psychostimulants pemoline, fenozolone and thozalinone in human urine by gas chromatography/mass spectrometry and thin layer chromatography.

Detection of the psychostimulants pemoline (Tradon), fenozolone (Ordinator) and thozalinone (Stimsen) in biological samples (urine) presents certain experimental difficulties. These substances were therefore converted by acid hydrolysis to their common hydrolysis product 5-phenyl-2,4-oxazolidinedione, which can be detected with high sensitivity and selectivity by thin layer chromatography. After silylation with N-methyl-N-trimethylsilyltrifluoroacetamide/trimethylchlorosilane quantitative results can be obtained from the same extract by the proposed GC/MS-method. After a single dose of 30 mg pemoline, levels ranging from one to four mg/l urine were observed.

[Investigations of clobazam (Frisium) by combined gas chromatography/mass spectrometry (author's transl)]. / Gaschromatographisch-massenspektrometrische Untersuchungen zur Analytik von Clobazam (Frisium).

Clobazam (Frisium) was hydrolyzed according to three methods commonly used in the determination of 1.4-benzo-diazepines; the reaction products were analyzed by gas chromatography/mass spectrometry and thin-layer chromatography. Five degradation products were obtained for which structure proposals are discussed. After oral intake two of these substances were also detected in human urine. It should be recognized that some of the above mentioned substances may be on-column degradation products of artifacts occurring during hydrolyzation and/or sample clean-up.

[Quantitative determination of mefexamide and its main degradation product desmethyl-mefexamide in human urine after ingestion of therapeutic doses (author's transl)]. / Die quantitative Bestimmung von Mefexamid und dessen Hauptmetaboliten Desmethyl-Mefexamid im menschlichen Harn nach Einnahme einer therapeutischen Dosis.

After oral ingestion of 400 mg Mefexamidehydrochloride for Mefexamide (I) and its main degradation product Desmethyl-Mefexamide (II) the following pharmakokinetic parameters have been determined: 1. Elimination of I and II follows 1st order kinetics. 2. Biological half-life t 1/2 for I is 4-6, for II 4.5-6.5 H. 3. Elimination rate constant for I and II is between 0.10 to 0.20 h-1. 4. 5-10% of the administered drug are excreted unchanged, 10-16% as Desmethyl-Mefexamide within 72 h after ingestion. 5. The described thinlayer chromatographic and gas chromatographic/mass spectrometric methods allow detection of I and II for at least 72 h after application. 6. II is excreted free and conjugated in nearly equal amounts.

[Biotransformation of doxylamine: isolation, identification and synthesis of some metabolites (author's transl)]. / Zum Stoffwechsel des Doxylamin: Isolierung, Identifizierung und Syntheseeiniger Metabolite.

After administration of therapeutic doses of doxylamine, the unchanged drug(I) and five degradation products were detected in human urine; their chemical structures are discussed and - to some extent - confirmed by synthesis. The results show that biotransformation of doxylamine in man takes place by the following routes: successive dealkylations at the nitrogen atom, giving N-demethyl-doxylamine(II) and N.N-didemethyl-doxylamine(II); cleavage at the benzhydrylether-function, resulting in the formation of 1-phenyl-1-(2-pyridyl)-ethanol(V), 1-phenyl-1-(2-pyridyl)-ethane(VI) and 1-phenyl-1-(2-pyridyl)-ethene(VII). VI and VII may be artefacts. Identification of an additional degradation product(=IV) was not possible, because the isolated quantities were too small. The analytical properties (hydrolysis!) of the pure substance and free base are thoroughly discussed, as well as the role of Chemical Ionization Mass Spectrometry with various reagent gases for the examination of biological extracts.

[FAB (fast atom bombardment)-mass spectrometry. A new study method in the hands of the (forensic) toxicologist]. / FAB (Fast Atom Bombardment)-Massenspektrometrie. Eine neue Untersuchungsmethode in der Hand des (forensischen) Toxikologen.

The FAB (Fast Atom Bombardment)-mass spectrometric ionization technique, which has now been available for about 1 year, has been successfully employed in forensic toxicology. The mass spectral behaviour of some representative drug-glucuronides (Codeine, p-Nitrophenol and 2-Phenyl-1-propanol) were studied by positive- and negative-ion-FAB-MS. The presented promising results may be of some interest, not only for the analytical toxicologist.

[Analysis and renal excretion of pirisudanol (Stivane)]. / Zur Analytik und renalem Ausscheidungsverhalten von Pirisudanol (Stivane).

The chromatographic and spectroscopic properties (TLC; UV; IR; 1H-NMR; GC/MS) of the psychostimulant Stivane (dimaleate;I) are presented in detail, describing some analytic peculiarities of the pure substance as well. Moreover, the results of the renal excretion studies are reported: after hydrolysis in each of the acidic and basic urine extracts a degradation product--but no unchanged drug--could be detected.

[On the metabolism of eprazinone (author's transl)]. / Zum Metabolismus von Eprazinon.

After oral application of 3-[4-(beta-ethoxyphenethyl)-1-piperazinyl]-2-methylpropiophenone dihydrochloride (eprazinone, Eftapan) together with the unchanged drug, five degradation products were detected and subsequently identified by gas liquid chromatography/mass spectrometry in human urine. With respect to the presented results, eprazinone is degraded by various routes in man: 1. hydrolysis which leads to metabolites M1 and M4, and 2. cleavage of alpha-binding to the nitrogen atom and successive dealkylation reactions resulting in M2, M3 and M5, respectively.

Quantitative determination of diphenhydramine and orphenadrine in human serum by capillary gas chromatography.

Diphenhydramine has been in medical use for 35 years as an antihistamine and hypnotic. We evaluated the pharmacokinetic parameters, which are not only important for disposition studies, in the serum of 10 volunteers who received a single dose of 31 mg diphenhydramine. For this purpose a suitable capillary GC-method was developed, which has a detection limit of 2 micrograms/l (serum); the calibration curve is linear between 2.5 and 120 micrograms/l, the reproducibility is always better than 3.6% and the average recovery is about 100.1%. The combination of a relatively non-polar extraction solvent, a selective detector (N-FID) and a fused silica, bonded-phase capillary column led to a more rapid sample clean-up procedure (no back-extraction needed) and is sensitive and specific enough for the quantitative determination of diphenhydramine, orphenadrine or other ethanolamines in human serum.

[Isolation and identification of some metabolites of mephenoxalone (Control-OM) from human urine (author's transl)]. / Isolierung einiger Metaboliten des Mephenoxalone (Control-OM) aus menschlichem Harn und ihre Identifizierung

Mephenoxalone (5-(o-methoxyphenoxymethyl)-2-oxazolidone) is degraded by various routes in the human, and some is excreted unchanged. In the metabolism of mephenoxalone, the phenoxymethyl ether bond is cleaved; thus o-methoxyphenol (metabolite I) was identified in urine, and 3-amino-1,2-propanediol (IIa) was found after alkaline hydrolysis. Hydroxylation of the benzene ring produces a phenolic hydroxymephenoxalone (metabolite III), and demethylation converts mephenoxalone into demethylmepheonxalone (metabolite IV). Opening of the oxazolidone ring leads to the production of 1-(o-methoxyphenoxy)-3-aminopropane-2-ol(metabolite V). Urine contains two further substances: 1-(o-hydroxyphenoxy)-3-aminopropene (metabolite VI) and dehydromephenoxalone (metabolite VII). Metabolite VI may be an artefact. Compounds III, IV and VII could only be detected after acid hydrolysis and enzymic cleavage with beta-glucuronidase/aryl sulphatase, whereas V and VI were detected only after acid hydrolysis. Thin layer chromatography revealed three further metabolites, which were not identified.

[Biotransformation of zipeprol (Mirsol) in humans. Gas chromatographic/mass spectrometric studies, using ammonia as a selective reactant gas (author's transl)]. / Zur Biotransformation von Zipeprol (Mirsol) beim Menschen: Gaschromatographisch/massenspektrometrische Untersuchungen mit Ammoniak als selektivem Reaktandgas.

After oral application of Zipeprol (Mirsol) the unchanged drug and nine degradation products were detected in human urine; six of them could be identified. All identified metabolites were detected in the alkaline urine fraction; after acid hydrolysis N-(2-hydroxyethyl)-piperazine was found as an artifact. With respect to the presented results, biotransformation of Zipeprol in man mainly follows three degradation routes: 1. alpha-cleavage leading to metabolite M4; 2. cleavage of the exocyclic N-C-bond of the piperazine ring leading to metabolites M3, M5, M6; 3. benzylic cleavage leading to benzylalcohol (M1); oxidation leading to 2-hydroxy-2-phenylacetic acid (mandelic acid, M2).

[Detection of pentazocin (Fortral) in human urine: gas chromatographic/mass spectrometric studies]. / Zum Nachweis von Pentazocin (Fortral) im menschlichen Harn: Gaschromatographisch/massenspektrometrische Untersuchungen.

After oral application of pentacozine (Fortral) besides the unchanged drug some further excretion products were detected by glc/ms in human urine. For their identification e.i.-and c.i.-mass-spectrometry as well as the just recently available FAB-technique were employed. All analyses were performed on a VG-Micromass 7035; the samples were introduced in the ion source via a fused silica, bonded phase capillary column (30 metres; DB-1 J + W, Inc.). The analytical profiles of the pure substance and some metabolites are reported as well as the behaviour of the pure substance on acidic hydrolyzation.

[Pharmacokinetics and bioavailability of diphenhydramine in man]. / Pharmakokinetik und Bioverfügbarkeit von Diphenhydramin beim Menschen.

By the presented study the relative bioavailabilities and some important pharmacokinetic parameters should be evaluated after oral application of a single-dose of three different diphenhydramine (DPH, 2-diphenylmethoxy-N,N-dimethylethylamine)preparations in a randomized, cross-over design to 12 healthy volunteers. Additionally, some simple pharmacodynamic measurements of the volunteer's vigilance were performed and the question whether a combination with 8-chlorotheophylline influences the pharmacokinetic and/or pharmacodynamic profile of DPH was investigated. As the test preparations (Benocten as a tablet = A, as a buffered solution = B) contained 50 mg of DPH-HCl, but the reference preparation (= C) only 31 mg of DPH-HCl (+ 23 mg 8-chlorotheophylline), the biometric-statistic calculations had to be done with and without dose correction. Bioequivalence of the preparations could only then be demonstrated when the calculations were done with dose corrections: without these corrections for the reference preparation significantly lower serum levels resulted which hardly can be considered sufficient for exerting a sleep-inducing effect. The addition of 8-chlorotheophylline recommended by some other authors for an enhanced sedative effect could not be substantiated by our results. Peak serum levels of 61 and 53 ng/ml, respectively, for the test preparations and 40 ng/ml for the reference preparation were reached after 2.0 to 2.5 h p.a.; elimination half-lives were between 4 and 6 h. A statistically significant positive correlation could be found for AUC (0-24 h) and the amount excreted in urine in the same period of time, as higher mean serum levels were correlated with higher amounts excreted renally.(ABSTRACT TRUNCATED AT 250 WORDS)

Irbesartan does not affect the steady-state pharmacodynamics and pharmacokinetics of warfarin.

OBJECTIVES: To determine whether the initiation or titration of irbesartan alters the pharmacodynamics and/or pharmacokinetics of warfarin in a clinically significant manner, thereby requiring additional monitoring of the anticoagulant effect of warfarin. METHODS: Daily doses of warfarin were administered to 16 healthy males for 21 days (10 mg on day 1 and 2.5-10 mg on days 2-21). Irbesartan (300 mg/day) or placebo was concomitantly administered on days 15-21. The pharmacodynamic parameters prothrombin time (PT) and prothrombin time ratio (PTR) were evaluated throughout the study. Plasma and urine samples were collected before and up to 24 h after administration on days 14, 15 and 21 for the determination of the maximum concentration (C(max)), time to reach C(max)(t(max)), the area under the concentration-time curve (AUC) of S-warfarin and the cumulative urinary excretion of warfarin and its metabolites. Pre-dose plasma samples were also collected to determine the C(min) of S-warfarin (days 12, 13, 14 and 21) and irbesartan (days 19, 20 and 21). RESULTS: Analysis of PTR data revealed no significant difference between the group mean PTR values at day 22 and those at day 15 (P=0.699). S-warfarin concentrations in plasma and urine, as well as the urinary concentrations of the metabolites of warfarin, were not affected by concomitant single- or multiple-dose administration of irbesartan. Plasma C(min) concentrations of S-warfarin and irbesartan were also not affected. CONCLUSIONS: No clinically important effect of irbesartan on the pharmacodynamics and pharmacokinetics of warfarin are likely to occur during concomitant administration; therefore, neither a dosage adjustment of irbesartan or warfarin nor any additional monitoring of the anticoagulant effect of warfarin is necessary.

[Comparative test of the bioavailability and pharmacokinetics of 2 oxazepam preparations using high-pressure liquid chromatography]. / Vergleichende Prüfung der Bioverfügbarkeit und Pharmakokinetik zweier Oxazepam-Präparate mit Hilfe der Hochdruckflüssigkeitschromatographie.

The relative bioavailability and pharmacokinetic profile of two oxazepam preparations were evaluated in 12 normal volunteers by a newly developed HPLC-method. After oral application of one tablet of the test (Noctazepam) and reference preparation, respectively, no statistically significant differences of the AUC, Cmax Tmax and t1/2 were found. As compared to the reference preparation the relative bioavailability of the test preparation as 110%; both preparations are therefore bioequivalent.

Quantitative determination of bencyclane in human plasma by capillary gas chromatography/chemical ionization mass spectrometry.

Since 10 years there is a phenomenal increase in the use of mass spectrometry, combined with (capillary-) gas chromatography and dedicated data systems for the rapid, reliable, sensitive and selective determination of xenobiotics (drugs, their degradation/biotransformation products etc.) in biological fluids. This applies especially since the introduction of newer developments in ionization techniques (CI, DCI, FAB) and gas chromatographic column technology (fused silica, bonded phase columns). We employed such a sophisticated method for the quantitative determination of N-[3-(1-benzyl-cycloheptyl-oxy)-propoxy]-N,N'- dimethylammoniumhydrogen fumarate (bencyclane) in human plasma after oral application of a therapeutic doses. Our results clearly show that this approach is the best method available; furthermore the detected plasma levels will lead to discussions with respect to the pharmacokinetic properties of the drug.