Stability, blood partition, and pharmacokinetics of a new proton pump inhibitor, YJA-20379-8.
Stability, blood partition, and pharmacokinetics (including tissue distribution and biliary excretion) of YJA-20379-8 were studied using an HPLC analysis. YJA-20379-8 was stable for up to 48 h incubation in a water-bath shaker kept at 37 degrees C and at a rate of 50 oscillations per min in pH solutions ranging from 1 to 14. YJA-20379-8 rapidly reached equilibrium between plasma and blood cells of three rabbit blood, and the equilibrium plasma to blood cell concentration ratios were independent of the initial YJA-20379-8 blood concentrations; the mean values were 1.42-1.56 for three rabbit blood at initial YJA-20379-8 blood concentrations of 1-5 micrograms/ml. As expected from blood partition of the drug between plasma and blood cells, there was no in vitro 'blood storage effect' of YJA-20379-8. After intravenous administration of YJA-20379-8, 10, 20, and 50 mg/kg, to rats, the values of t1/2, MRT, Vss, and CL were dose-independent. However, after intravenous administration of the drug, 5, 10, and 20 mg/kg, to rabbits, the values of t1/2, MRT, and Vss were dose-dependent. After oral administration of the drug, 20, 50, and 100 mg/kg, to rats, the F values (9.00, 16.7, and 11.3% for 20, 50, and 100 mg/kg, respectively) were low considering considerable absorption of the drug from rat gastrointestinal tract (98, 80, and 76% for 20, 50, and 100 mg/kg, respectively) and this could be due to hepatic, gastric, and/or intestinal first-pass metabolism. YJA-20379-8 was under detection limit in urine samples and the contribution of biliary excretion of unchanged YJA-20379-8 to nonrenal clearance of the drug was negligible (less than 0.5% of intravenous dose) in rats, suggesting that the CL (or nonrenal clearance) of YJA-20379-8 could represent metabolic clearance in rats. YJA-20379-8 had a good affinity to almost all rat tissues studied and this was supported by a relatively high value of Vss (3.93-3.93 ml/kg) after intravenous administration of the drug to rats.
Chung
S Y
SY
College of Pharmacy, Seoul National University, South Korea.
Han
K S
KS
Chung
Y K
YK
Chang
M S
MS
Lee
M G
MG
D000284:Administration, Oral; D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006207:Half-Life; D007262:Infusions, Intravenous; D008297:Male; D009287:Naphthyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D054328:Proton Pump Inhibitors; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
C114511:3-butyryl-4-(5R-methylbenzylamino)-8-ethoxy-1,7-naphthyridine; D000897:Anti-Ulcer Agents; D009287:Naphthyridines; D054328:Proton Pump Inhibitors