The biliary and renal elimination of the new muscarinic-1-antagonist AWD 26-06 were investigated in 6 female volunteers (age: 26-69 years) 9-14 days after cholecystectomy and T-tube construction. After a single oral dose of 50 mg AWD 26-06 as an aqueous solution the amount of the unchanged substance was determined in serum, T-tube bile and urine with a special HPLC-method. The concentration maximum was reached earlier and higher in bile (60 +/- 22 min; 10.8 +/- 5.7 micrograms/ml) than in serum (73 +/- 28 min; 0.98 +/- 0.53 micrograms/ml). During the whole observation time of 24 h the AWD 26-06 concentration in bile was 2-21-fold higher than in serum. In mean 2.3 +/- 1.5% of the administered dose were eliminated unchanged by bile and 12.2 +/- 5.9% by urine. More than 70% of the dose were metabolized. The results gave a hint at active liver transport processes and an enterohepatic recirculation. A drug interaction was observed with valproic acid on the metabolic level. The great interindividual variability of pharmacokinetic data can be caused by the heterogeneity of the subject group and a genetic polymorphism in the metabolism of AWD 26-06. The bile sampling by means of a T-tube is a simple but effective method under consideration of special conditions.

01 Jan 1992·Die PharmazieQ4 · MEDICINE

[The pharmacokinetic behavior of AWD 26-06 in humans following single and multiple administration].

Q4 · MEDICINE

Article

Author: Richter, K ; Feller, K ; Terhaag, B

The pharmacokinetics of the muscarinolytic drug AWD 26-06 was investigated in two subjects after a single dose of 50 and 100 mg, respectively, and with six subjects after repeated dosage. The half time (t1/2) is 2.4 and 2.6 h, respectively, the height of the concentration maximum (Cmax) 500 and 1400 ng.ml-1, respectively, and the area under the curve (AUC) 2155 and 4334 ng.ml-1.h, respectively. The repeated dosage (25 mg every 8 h for 7 d) showed a small increase of the serum level. The t1/2 and the mean residence time (MRT) at the 1st and the 8th d are 2.6 h (range: 1.8-2.9 h) and 4 h (range: 2.7-5.8 h), respectively. The point (tmax) and the Cmax were not different at the 1st and 8th d: mean tmax (1st d) 1.1 h (range: 1.0-1.5 h), mean tmax (8th d) 0.9 h (range: 0.75-1.0 h); Cmax (1st d) 227 ng.ml-1 (range: 160-320 ng.ml-1), Cmax (8th d) 282 ng.ml-1 (range: 168-320 ng.ml-1). There were also no differences for the AUC0-t at the 1st and 8th d (1st d) 815 ng.ml-1.h (range: 610-1134 ng.ml-1.h). The simulation of the serum level by means of the data from the single dose were established by this investigation. Typical subjective muscarinolytic symptoms (e.g. dryness of the mouth, diminution of accommodation) were observed after the 2nd/3rd dosage. These signs diminished 24-36 h after discontinuation of the dosage. The parameter ALAT, proteins of plasma, and blood cell count were not changed at the end of therapy in comparison to the beginning.

01 Jul 1990·Die PharmazieQ4 · MEDICINE

[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].

Q4 · MEDICINE

Article

Author: Pfeifer, S ; Gedan, A ; Klemm, W ; Joram, U ; Zerjatke, W ; Morgenroth, U

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.

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