Dose-independent pharmacokinetics of a new reversible proton pump inhibitor, KR-60436, after intravenous and oral administration to rats: gastrointestinal first-pass effect.
Dose-independent pharmacokinetic parameters of KR-60436, a new proton pump inhibitor, were evaluated after intravenous (i.v.; 5, 10, and 20 mg/kg) and oral (20, 50, and 100 mg/kg) administration to rats. The hepatic, gastric, and intestinal first-pass effects were also measured after iv, intraportal (i.p.), intragastric (i.g.), and intraduodenal (id) administrations to rats of a dose of 20 mg/kg. The areas under the plasma concentration-time curve from time to zero to time infinity (AUCs) were independent of iv and oral dose ranges studied; the dose-normalized AUCs were 83.0-104 microg. min/mL (based on 5 mg/kg) and 78.4-96.8 microg. min/mL (based on 20 mg/kg) for iv and oral administration, respectively. After an oral administration at a dose of 20 mg/kg, approximately 3% of the oral dose was not absorbed, and the extent of absolute oral bioavaliability (F) was estimated to be 18.8%. The AUCs of KR-60436 after i.g. and i.d. administration at a dose of 20 mg/kg were significantly smaller (82.4 and 57.5% decrease, respectively) than that after an i.p. administration at a dose of 20 mg/kg, suggesting that gastrointestinal first-pass effect of KR-60436 was approximately 80% of oral dose in rats (the gastric first-pass effect was approximately 25%). After an i.p. administration at a dose of 20 mg/kg, the AUC was 77.6% of an iv administration, suggesting that hepatic first-pass effect was approximately 22% of KR-60436 absorbed into the portal vein. Note that the value of 22% was equivalent to approximately 4% of the oral dose. Because only 17% of oral dose was absorbed into the portal vein, the low F of KR-60436 in rats was mainly due to considerable gastrointestinal first-pass effect, which was approximately 80% (the gastric first-pass effect was approximately 25%) of oral dose.
Yu
Su Yeon
SY
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Bae
Soo Kyung
SK
Kim
Eun Jung
EJ
Kim
Yoon Gyoon
YG
Kim
Sun-Ok
SO
Lee
Dong Ha
DH
Lim
Hong
H
Lee
Myung Gull
MG
D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D054328:Proton Pump Inhibitors; D017494:Proton Pumps / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D011804:Quinolines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
C439392:1-(2-methyl-4-methoxyphenyl)-4-((2-hydroxyethyl)amino)-6-trifluoromethoxy-2,3-dihydropyrrolo(3,2-c)quinoline; D054328:Proton Pump Inhibitors; D017494:Proton Pumps; D011758:Pyrroles; D011804:Quinolines