Pharmacokinetics of a New Proton-pump Inhibitor, YJA-20379-8, after Intravenous and Oral Administration to Rats with Streptozotocin-induced Diabetes Mellitus

Abstract

Because physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics of the drugs used to treat the disease, the pharmacokinetics of a new proton pump inhibitor, YJA-20379-8, were investigated after intravenous and oral administration of the drug (50 mg kg−1) to control rats and to rats with streptozotocin-induced diabetes mellitus (SIDM).After intravenous administration of YJA-20379-8 to SIDM rats, plasma concentrations of the drug were significantly higher and this resulted in a significantly greater AUC (area under the concentration-time curve; 2520 ± 366 compared with 1870 ± 272 min mL−1). This was because of significantly slower clearance (CL; 19.5 ± 2.88 compared with 27.2 ± 3.93 mL min−1 kg−1) in SIDM rats. The significantly slower metabolism of YJA-20379-8 in SIDM rats was confirmed by an in-vitro tissue metabolism study; the amounts of YJA-20379-8 remaining in the liver (27.1 ± 5.19 compared with 18.9 ± 8.24 μg (g tissue)−1) were significantly greater after 30-min incubation of the drug (50 μg) with supernatant fractions obtained from the tissues by centrifugation at 9000 g. After oral administration of YJA-20379-8 to SIDM rats the plasma concentrations of the drug were significantly lower and this resulted in significantly smaller AUC (128 ± 31.0 compared with 219 ± 45.6 μg min mL−1). This was because of reduced gastrointestinal absorption of YJA-20379-8 in SIDM rats; the amounts of the oral dose recovered as unchanged drug from the entire gastrointestinal tract after 24 h were significantly greater (32.9 compared with 19.2%) in SIDM rats.The tissue distribution of YJA-20379-8 was not affected by SIDM.