On the complex formation of acridine dyes with DNA. VII. Dependence of the binding on the dye structure.
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Acridines↗
Biomedical subjects
G Achtert
Publications and source records attributed to G Achtert.
Steady state investigation of possible pharmacokinetic interactions of moxonidine and glibenclamide.
The aim of the study presented here was to determine possible pharmacokinetic interactions of moxonidine and glibenclamide at steady state in 18 healthy male volunteers. Multiple oral doses of 0.2 mg of moxonidine b.i.d. (q. 12 h) and of 2.5 mg of glibenclamide o.i.d. (q. 24 h) were administered alone and in combination in an open, non-randomized, three-treatment design. The preparations were given for 5 days in each of the 3 periods. The results of this multiple dose study did not indicate substantial pharmacokinetic interactions of the drugs. Regarding the influence of glibenclamide on the pharmacokinetics of moxonidine, no significant changes were seen at all. In the presence of moxonidine, a minor decrease of bioavailability of glibenclamide was detectable, as could be derived from the AUC and clearance data. The actual differences were small and not considered to be of clinical significance.
Administration, Oral↗
[Pharmacokinetics and biotransformation of N-propylajmaline hydrogen tartrate in man].
10 and 20 mg of N-Propyl-ajmalin-hydrogentartrate (N-PAB, Neo-Gilurytmal) were administered i.v. and orally respectively to healthy volunteers. In the study 14C-labelled N-PAB was used. The pharmacokinetics and the metabolic behaviour was examined. A fast and complete absorption of the compound could be observed. The bioavailability was 78%. The terminal plasma elimination half-life (beta-phase) was in the range of 4 to 6 hours. A total of 33% of the administered radioactivity was excreted via the kidney. 35 to 48% of the radioactivity found in urine was unchanged N-PAB. The excretion-kinetics of the three main metabolites as well as of the parent compound were determined. The possible presence of non-metabolizers is suggested.
Adult↗
Metabolism and pharmacokinetics of metaclazepam (Talis), Part III: Determination of the chemical structure of metabolites in dogs, rabbits and men.
The metabolism of 7-bromo-1-methyl-2-methoxymethyl-5-(2'-chlorophenyl)-2, 3-dihydro-1H-1,4-benzodiazepine (metaclazepam, Talis) in animals and men is described. Based upon mass spectrometry fifteen metabolites could be identified. Qualitative and quantitative differences in the biotransformation products of metaclazepam in comparison with the well known metabolites of other drugs in the 1,4-benzodiazepine class could be demonstrated. Metabolites with a benzodiazepine-2-one structure representing the most characteristic feature of other 1,4-benzodiazepines and their metabolites, were found in trace amounts only. The major metabolic pathways of metaclazepam led via stepwise demethylation of the O-methyl and/or the N-methyl group to O-demethyl-metaclazepam (M 2), N-demethyl-metaclazepam (M 7) and bis-demethyl-metaclazepam (M 6). Further aromatic hydroxylation yielded the metabolite M 1. Two metabolites with amino-benzophenone structure (M 5, M 8) which are in general known to result from other 1,4-benzodiazepines could be detected. Additionally a 3-oxo-benzodiazepine (M 4) was found. Minor biotransformation pathways led to a chlorophenyl-bromo-benzodiazepine (M 9) by loss of the side chain from bis-demethyl-metaclazepam and N-demethyl-metaclazepam. By further oxidation and degradation the 2-oxo-benzodiazepine M 10 and the dihydro-quinazoline M 12 were formed. The respective N-methylated metabolites M 13 and M 16 were possibly generated by the same pathway. Still open is the formation of M 15, a 1-methyl-3-hydroxy-4-(2'-chlorophenyl)-6-bromo-1,2-dihydroquinoline and M 11, a 2-methyl-4-(2'-chlorophenyl)-6-bromo-quinazoline. The substitution of bromine by a hydroxyl group during the formation of M 14 can be explained by a NIH-shift mechanism. Quantitative investigations show that the methoxymethyl side chain in the benzodiazepine ring system of metaclazepam acts as an effective barrier with respect to the metabolic attack at position two. We assume that this barrier only can be overcome by complete side chain degradation. This multi-step reaction can hardly compete with more favourable and faster conjugation and elimination processes.
Adult↗
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).
Adult↗
Pharmacokinetics of n-propyl-ajmaline-bitartrate in elderly patients with ventricular ectopic activity.
11 patients (9m, 2f, median age 59 years) with ventricular ectopic activity of at least Lown grade III received 20 mg N-Propyl-ajmaline-bitartrate (N-PAB) p.o. Plasma concentrations of N-PAB were determined with HPLC from blood samples within 26 hours after administration. An open two-compartment model was used. In 8 patients with normal function of the liver and the kidneys, the median clearance of N-PAB was 6.86 ml/min/kg and the median volume of distribution was 1.56 l/kg. Two patients had a clearly diminished clearance of 1.58 ml/min/kg without obvious impairment of liver or renal function. One patient with chronic glomerulonephritis (plasma creatinine 3.4 mg/dl) had a N-PAB clearance of 2.79 ml/min/kg. None of the Spearman rank correlation coefficients between the pharmacokinetic parameters of N-PAB with age, plasma albumin/globulin-quotient, plasma creatinine and cholin-esterase were significant. All calculated parameters were in the range determined in young subjects. It is concluded that physiological changes with age do not lead to significant changes of the pharmacokinetics of N-PAB. On the other hand in patients with increased levels of plasma creatinine a diminished clearance of N-PAB can be expected. It is also possible that patients without an obvious impairment of liver or renal function may have diminished N-PAB clearance.
Aged↗
Pharmacokinetics and metabolism of 14C isobytylnaphtyl acetic acid in rat.
After oral administration to rats, absorption of INAA was slow but complete. Plasma level curves reached a plateau for INAA as well as for the two metabolites, which were rapidly formed (MI and MII). The plateau concentration led to an increase of the apparent elimination half-life, which was short after i.v. administration due to the small volume of distribution and to the high rate of metabolism. In any case the half-life was independent of the dose and the pharmacokinetics of INAA remained linear from 1.5 to 15 mg/kg. The two rapidly formed plasma metabolites were eliminated more slowly than INAA. INAA and its metabolites were distributed only sparsely in all tissues under investigation, probably due to the high protein binding. Both routes of administration resulted in elimination of the radioactivity mainly by the urine. Besides the two main metabolites with known structures (MI and MII) small amounts of INAA and two additional metabolites were detected.
Administration, Oral↗
Pharmacokinetics/bioavailability of colchicine in healthy male volunteers.
In a randomized 2-way cross-over study with twelve healthy male volunteers, two colchicine preparations (tablets, A vs. oral solution, B) were tested. The preparations were administered as single doses of 1 mg; prior to and up to 72 h after medication blood samples were collected and the plasma colchicine concentrations determined. Additionally urine samples were collected at 0-2, 2-4, 4-6, 6-8, 8-10, 10-24, 24-48, 48-72 and 72-96 h intervals. The colchicine plasma and urine concentrations were determined by a newly developed and validated RIA method. The mean area under the plasma concentration-time curve (AUC-1, AUC-3) was calculated as 23.95 +/- 12.10 (AUC-1) and 26.73 +/- 12.75 (AUC-3) h.ng/ml after application of A and 28.01 +/- 14.74 (AUC-1) and 31.57 +/- 16.58 (AUC-3) h.ng/ml after application of B, respectively. Mean peak plasma concentrations of 4.15 +/- 2.35 (A) and 4.88 +/- 3.90 (B) ng/ml were reached at 1.15 +/- 0.38 (A) and 1.13 +/- 0.42 (B) h after application. The mean terminal half-lives accounted for 9.31 +/- 3.98 (A) and 10.57 +/- 5.53 (B) h. The mean total clearance (Cl/F) and volume of distribution (V/F) were found to be 40.12 +/- 20.87 (A) and 46.58 +/- 24.65 (B) l/h and 472.59 +/- 196.46 (A) and 624.89 +/- 304.09 (B) l, respectively. The mean total amount excreted in urine (Ae) was 172.66 +/- 91.51 (A) and 174.85 +/- 63.53 (B) micrograms.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Metabolism of isobutylnaphthyl acetic acid in rats: determination of the chemical structures of metabolites.
After oral and intravenous administration of radiolabelled isobutylnaphthyl acetic acid (INAA) to rats two metabolites were isolated from urine and plasma by HPLC. Field desorption, high resolution electron impact mass spectrometry as well as GC-MS after derivatization were used for structure elucidation and identification of the metabolites. The main biotransformation product in rat urine was found to be 5-(2'-hydroxy-2'-methyl-propyl)-1-naphthyl acetic acid (M1). The main metabolite in plasma was derived and was found to be 5-(2'-carboxypropyl)-1-naphthyl acetic acid (M2).
Animals↗
Oral medium-dosed metoclopramide versus placebo as highly effective antiemetic prophylaxis in in- and outpatients on noncisplatin chemotherapy.
The antiemetic effect of oral medium-dosed metoclopramide (MCL, 3.5 mg/kg b.w./cycle) and placebo for chemotherapy-induced emesis of a noncisplatin regimen was assessed for inpatients and outpatients in two double-blind placebo-controlled sequential analyses according to Bross (1952). MCL was given in 5 single doses of 0.7 mg/kg b.w. at 0 h (loading) and at 2 h (i.e. start of chemotherapy) and 6, 10 and 14 h (as maintenance doses). Both studies ended after 8 sequential pairs in favor of MCL (2 alpha = 2 beta = 0.05). Major antiemetic protection (< 2 emetic episodes per 26 h) was achieved for 8/8 of inpatients and 7/8 of outpatients (placebo 0/8 and 0/8). Side effects neither required discontinuation of the antiemetic regimen nor additional therapy. The median of MCL plasma levels ranged from 150 to 750 ng/ml and terminal half-lives from 3.9 to 8.9 h.
Administration, Oral↗