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 microg 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 microg(g tissue)(-1)) were significantly greater after 30-min incubation of the drug (50 microg) 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 microg 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 24h were significantly greater (32.9 compared with 19.2%) in SIDM rats. The tissue distribution of YJA-20379-8 was not affected by SIDM.