Distribution behaviour of 131-iodine labelled trans-N,N'-bis-(ethoxy-carbonyl)-N-[4-(3-iodo-4-methoxyphenyl)butyl]-N' -5- phenylpentyl)-1,4-cyclohexanedimethanamine.
The title compound 9, which is a prodrug, and its active metabolite 7 were labelled with 131I (7*/9*) to investigate their pharmacokinetic behaviour, including the distribution between stomach, gut, muscle, blood, lung, liver, kidney, adrenal gland, heart, and spleen. Four hours after oral administration of 7* to mice only 3% of the dose had been absorbed from the g.i. tract. After 24 h 54% of the radioactivity still is found the gut, predominantly in the small intestine. These results explain why 7, which is a potent antiplatelet drug in vitro, shows no antithrombotic effect in vivo. In contrast, the produg 9/9* is absorbed considerably, i.e. up to 50% in 4 h from the g.i. tract depending on the dose applied and the vehicle used. At doses in the micromolar range the absorption appears to be diffusion limited. The highest concentrations are found in the liver and the kidneys suggesting a first pass effect of 7 followed by renal excretion. From the blood levels achieved, the dose necessary for an antithrombotic effect has been calculated to be about 100 mg/kg. In summary, the N-ethoxycarbonyl derivatives of oligoamines appear to be suitable prodrugs for oral administration of oligoamines.
Rehse
K
K
Institut für Pharmazie, Freien Universität Berlin, Berlin, Dahlem.
Wolf
S
S
Buck
W
W
Wenzel
M
M
D000818:Animals; D000925:Anticoagulants / Q000493:pharmacokinetics*; D003510:Cyclohexanes / Q000493:pharmacokinetics*; D005260:Female; D007408:Intestinal Absorption; D007457:Iodine Radioisotopes; D051379:Mice; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D051381:Rats; D014018:Tissue Distribution
D000925:Anticoagulants; D003510:Cyclohexanes; D007457:Iodine Radioisotopes; C097717:N,N'-bis(ethoxycarbonyl)-N-(4-(3-iodo-4-methoxyphenyl)butyl)-N'-(5-phenylpentyl)-1,4-cyclohexanedimethanamine; D010975:Platelet Aggregation Inhibitors