Pharmacokinetics and tissue distribution of a novel PDE5 inhibitor, SK-3530, in rats.
OBJECTIVE
To investigate the pharmacokinetic profile and tissue distribution of a novel phosphodiesterase type 5 inhibitor, 5-ethyl-2-{5-[4-(2-hydroxy-ethyl)-piperazine-1-sulfonyl]-2-propoxy-phenyl}-7-propyl-3,5-dihydro-pyrrolo(3,2-d)pyrimidin-4-one (SK-3530), in rats after administration of the (14)C-labeled compound.


METHODS
The pharmacokinetic parameters of SK-3530 were measured based on the total radioactivity and parent SK-3530 concentration in rat plasma after intravenous and oral administration. The tissue distribution of total radioactivity after a single oral administration of [(14)C]SK-3530 at a dose of 40 mg/kg was assayed. The plasma protein binding rates of SK-3530 were assessed by in vitro and ex vivo assay.


RESULTS
The total radioactivity profiles showed linear pharmacokinetics. The maximum plasma concentration and area under the curve of the parent SK3530 were 10%-20% compared to those of the total radioactivity. After the oral administration of [14C]SK-3530, the radioactivity was widely distributed in all tissues, and the tissue/plasma ratio of the radioactivity 1 h after administration was calculated as 0.5-2.6 with the exception of excretory organs. A relatively high penetration was shown in the adrenal glands, liver, and lung. In vitro and ex vivo plasma protein binding assay by ultrafiltration showed a considerably high binding rate of more than 97%.


CONCLUSIONS
SK-3530 was relatively well absorbed in the gastrointestinal tract and showed linear pharmacokinetics over the investigated dose range. SK-3530 had low oral bioavailability due to a high, first-pass metabolism.
Yoo
Hye-hyun
HH
Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, Seoul, Korea.
Kim
Nam-sun
NS
Im
Guang-jin
GJ
Kim
Dong-hyun
DH
D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000493:pharmacokinetics*; D011485:Protein Binding; D011744:Pyrimidinones / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000493:pharmacokinetics*; D014018:Tissue Distribution
C518762:2-(5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo(3,2-d)pyrimidin-4-one dihydrochloride; D001798:Blood Proteins; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011744:Pyrimidinones; D013450:Sulfones