Pharmacokinetics of picumast dihydrochloride in patients with liver cirrhosis.
In a randomized parallel group design the pharmacokinetics of picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarine++ + dihydrochloride) and its active metabolites M1 and M2 were studied after intravenous or oral administration of a single dose of 10 mg picumast dihydrochloride in two groups of 8 patients with liver cirrhosis. After intravenous administration, the terminal half-life of 65 h was about 4 times longer than in healthy subjects although the total body clearance of 87 ml/min was only 7.4% lower. The 3.6-fold increase in the steady-state volume of distribution (351 l) may be due to a higher uptake by the liver and other tissues and/or to a slower re-diffusion from these tissues into the circulation. Only negligible amounts of picumast dihydrochloride appeared in the urine. Picumast dihydrochloride is almost exclusively eliminated by hepatic metabolism. After oral administration peak concentrations were reached at 1.4 h; plasma elimination half-life was considerably longer (107 h), however, without being significantly different from i.v. administration. The two patient groups differed with respect to their drug metabolizing capacity, therefore the absolute biovailability could not be established. The maximum concentration of the metabolites was reached 1.4 to 3.4 h later than Cmax of the parent drug. As compared to healthy subjects the clearance of the metabolites appeared to the reduced to a greater extent than that of the parent compound, so that under steady-state conditions in patients with liver disease these active metabolites will contribute more to the overall therapeutic effect than in normal individuals. 10.4% to 12.8% of the dose were recovered from the urine als M1.(ABSTRACT TRUNCATED AT 250 WORDS)
Neugebauer
G
G
Department of Clinical Pharmacology, Boehringer Mannheim, GmbH Fed. Rep. of Germany.
Raedsch
R
R
Stiehl
A
A
Kaufmann
B
B
Besenfelder
E
E
Neubert
P
P
Walter-Sack
I
I
D000284:Administration, Oral; D000368:Aged; D003374:Coumarins / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006634:Histamine H1 Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011485:Protein Binding
D003374:Coumarins; D006634:Histamine H1 Antagonists; C063140:3-carboxylic acid-picumast; C063141:3-hydroxymethyl-picumast; C013373:picumast