[Biotransformation and excretion of Z-2-amino-5-chlorobenzophenoneamidinohydrazone]. / Biotransformation und Ausscheidung von Z-2-Amino-5-chlorbenzophenonamidinohydrazon.

After i.v., p.o. and i.p. administration of 14C-labeled Z-2-amino-5-chlorobenzophenoneamidinohydrazone (1) to male Wistar rats the total radioactivity is mainly excreted via faeces (80%). Within 3 to 4 d after administration 86 to 100% of the dose have been found in urine and faeces. Beside 1 and its E-isomer (2) we have detected in faeces of rats and rabbits the metabolites 3 (principal metabolite) and 4, in urine of rats additionally 5 and 6, and in urine of rabbits additionally 5 to 8. With regard to the results of high resolution mass spectrometry, UV, TLC and the hydrolyzability using beta-glucuronidase we can conclude that 3 and 4 are metabolites position isomerically hydroxylated at the unsubstituted phenyl group, 5 and 6 are the glucuronides of them, and 7 and 8 are the glucuronides of 1 and 2.

[The pharmacokinetics of Z-2-amino-5-chlorobenzophenoneamidinohydrazone in the rat]. / Untersuchungen zur Pharmakokinetik von Z-2-Amino-5-chlorbenzophenonamidinonhydrazon an der Ratte.

Model-independent and model-dependent pharmacokinetic parameters were determined from the course of total radioactivity in blood following single i.v., p.o. and i.p. administration of two different doses of Z-2-amino-5-chloro-14C-benzophenoneamidinohydrazone (14C-1). Following i.v. administration of 14C-1 the total radioactivity in blood exhibits dose-dependent pharmacokinetics. After i.v. administration of 1,4.10(-6) mol.kg-1 14C-1 the terminal half-life has been found with 7 h, whereas this value is 32 h after administration of 4,4.10(-5) mol.kg-1 to female rats and 18 h after administration of 3,1.10(-5) mol.kg-1 to male rats. The apparent volume of distribution increases when the dose is increased. Following p.o. administration of 1,4.10(-6) mol.kg-1 and 4,1.10(-4) mol.kg-1 14C-1 the extent of absorption amounts to 21 and 59%, respectively. This effect of dose is related to the dose-dependent prolongation of gastrointestinal passage. After i.p. administration of 14C-1 the rate and extent of drug absorption is high. The time course of total radioactivity in blood is similar to that after i.v. administration.

[Biotransformation and pharmacokinetics of AWD 26-06, 8-chloro-5,10-dihydro-5-[bis(2-hydroxyethyl)aminoacetyl]-11H-dibenzo[d, c][1,4]diazepin-11-one hydrochloride in the rat]. / Biotransformation und Pharmakokinetik von AWD 26-06, 8-Chlor-5,10-dihydro-5-[bis(2-hydroxyethyl)aminoacetyl]-11H- dibenzo[d,c][1,4]diazepin-11-on-hydrochlorid an der Ratte.

After p.o. administration to rats AWD 26-06 (1) is rapidly but incompletely absorbed. The relatively short distribution (t1/2 alpha = 37 min) is followed by a middle-long elimination (t1/2 beta = 14 h). The volumen of distribution do not suggest an uncommon accumulation in deep compartments. About 70% of 1 were excreted unchanged with the feces. In urine and feces 18 metabolites were identified. The structure of 10 products could be elucidated. All metabolites have changed side-chains. Furthermore, the tricyclic molecule without side-chain and a N-methyl derivative were identified. The metabolites with so far unknown structure contain the unsubstituted tricyclic moiety too.

[Biotransformation and pharmacokinetics of AWD 26-06, 8-chloro- 5,10-dihydro-5-[bis(2-hydroxyethyl)aminoacetyl]-11H-dibenzo[b,c] [1,4]diazepin-11-one hydrochloride, in the rat]. / Pharmakokinetik von AWD 26-06, 8-Chlor-5,10-dihydro-5-[bis(2- hydroxyethyl)aminoacetyl]-11H-dibenzo[b,e][1,4]diazepin-11-on- hydrochlorid an der Ratte.

Following p.o. and i.v. application of the 14C-labelled AWD 26-06 (6 mg/kg b.w.) with anticholinergic activity, blood levels (-24 h) and excretion (urine, feces-72 h; bile-7 h) were studied in Wistar rats. Intestinal absorption amounted to 30% of the dose administered in water solution. Elimination half-lives in blood were 0.6 h and (after Cmax 3-4 h p.a.) 8 h. Excretion was mainly by feces (unchanged drug and biliary excreted metabolites) and to less extent by urine.

[The metabolism of bonnecor]. / Metabolizm bonnekora.

Bonnecor metabolism in the rat urine was studied. The main metabolites of bonnecor were identified by means of chromatography-mass-spectrometry.

[The pharmacokinetics and metabolism of bonnecor in rats]. / Farmakokinetika i metabolizm bonnekora u krys.

The pharmacokinetics of 14C-bonnecor after intravenous and oral administration was studied. The bioavailability was 70%. It was shown that administration of doses in the range of from 3 to 43 mg/kg as well as the repeated use of bonnecor failed to influence the pharmacokinetic parameters.

[Pharmacokinetics and metabolism of 3-carbethoxyamino-5-dimethylamino-acetyl-iminodibenzyl hydrochloride (Bonnecor, AWD 19-166, GS 015) in the rat]. / Pharmakokinetik und Metabolisierung von 3-Carbethoxyamino-5-dimethylamino-acetyl-iminodibenzyl-hydrochlorid (Bonnecor, AWD 19-166, GS 015) an der Ratte.

Excretion, blood level, distribution, and metabolite samples were studied on the rat after application of GS 015 marked by 14C. The compound is quickly and completely absorbed and metabolized from an aqueous solution. The marked substances form a broad blood level maximum, at the occasion of which a main metabolite distinguishes itself apart from the initial compound at first provable yet. The elimination half-life from the blood is 6 h. An intense influx of radioactive substance into the tissues takes place. The excretion of the marked metabolites occurs mainly renally making appear a second main metabolite. Striking sex differences are partly observed in the parameters tested.

[Pharmacokinetics and pharmacodynamics of 3-carbethoxyamino-5-dimethylamino-acetyl-iminodibenzyl hydrochloride (Bonnecor, AWD 19-166, GS 015) in the dog]. / Pharmakokinetik und Pharmakodynamik von 3-Carbethoxyamino-5-dimethylamino-acetyl-iminodibenzyl-hydrochlorid (Bonnecor, AWD 19-166, GS 015) am Hund.

The antiarrhythmic action of GS 015 was studied in proportion to its plasma concentrations ascertained in parallel, making use of the model of the two-step coronary ligature in the conscious dog. Blood levels of 1.0 microgram/ml (2 mg/kg i.v.) or of 0.8 microgram/ml (5 mg/kg orally) brought about a complete suppression of ectopic arrhythmias. The limit concentration for this effect is about 0.5 microgram/ml.