Pharmacokinetics of nisoldipine. II. Distribution to and elimination from tissues and organs following single or repeated administration of [14C]nisoldipine to rats and dogs.
(+/-) 3-Isobutyl-5-methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate (nisoldipine, Bay k 5552) labelled with 14C was administered to male rats, pregnant and lactating rats as well as female dogs with single intravenous (1.0 or 0.5 mg.kg-1) or oral doses (5 mg.kg-1) and with repeated oral doses of 5 mg.kg-1 to male rats for 3 weeks. The distribution to organs and tissues, the placental transfer and the secretion into milk was studied using whole body autoradiographic methods and/or quantitative determination of total radioactivity after autopsy, [14C]nisoldipine was distributed rapidly and heterogenously to organs and tissues. In the initial distribution phase following intravenous administration high concentrations compared to blood were found in heart muscle, brain, lung, adrenal cortex, kidney, and the intestinal mucosa. After single oral administration and at later time points after intravenous administration only liver and kidney contained higher radioactivity concentrations compared to plasma. Elimination from most of the organs occurred quite uniformly with half-lives of 40-70 h. There was no indication for distinct differences in the distribution pattern between rats and dogs. Following a 21-day oral treatment of male rats the equivalent concentrations in most of the tissues were increased by factors of 5 to 11. This factor was higher in the adrenal gland (15) and adipose tissue (19). The residues in the body after repeated administration were eliminated with a terminal half-life of about 10 days. No indication was found for a distinct retention of substance-associated radioactivity in organs and tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
Ahr
H J
HJ
Institute of Pharmacokinetics, Bayer AG, Wuppertal, Fed. Repb. of Germany.
Krause
H P
HP
Suwelack
D
D
Weber
H
H
D000284:Administration, Oral; D000818:Animals; D001345:Autoradiography; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004285:Dogs; D005260:Female; D007275:Injections, Intravenous; D007774:Lactation / Q000378:metabolism; D008297:Male; D008431:Maternal-Fetal Exchange; D008892:Milk / Q000378:metabolism; D009543:Nifedipine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015737:Nisoldipine; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*
D002121:Calcium Channel Blockers; D014665:Vasodilator Agents; D015737:Nisoldipine; D009543:Nifedipine