Meropenem, a carbapenem antibiotic, is inactive after oral administration and administered exclusively by injection. In this study, in order to address the factors involved in the oral inactivity of meropenem, in vitr...Meropenem, a carbapenem antibiotic, is inactive after oral administration and administered exclusively by injection. In this study, in order to address the factors involved in the oral inactivity of meropenem, in vitro permeation characteristics across rat ileal segments was investigated using diffusion cells. Moreover, stability of meropenem was evaluated in the Japanese Pharmacopoeia (JP) 1st and 2nd fluid for disintegration test. Cefotaxime, ceftibuten, and faropenem were used for comparison. The permeation of meropenem across rat ileal segments was approximately 5-fold greater in secretory direction than in absorptive direction. The secretory-oriented transport of meropenem markedly diminished by replacement of D-glucose in the experimental medium with unmetabolizing 3-O-methyl-D-glucose, suggesting that the secretory transport of meropenem was an energy-dependent process. Cefotaxime exhibited extensively secretory-oriented permeation. On the other hand, much weaker directionalities were observed in ceftibuten and faropenem. While meropenem as well as other three β-lactam antibiotics was stable in JP 2nd fluid (pH 6.8), it declined rapidly in JP 1st fluid (pH 1.2). These results suggest that, in addition to the hydrophilic property of meropenem, its instability at gastric pH and secretory transport in the small intestine are possible factors involved in the inactivity of meropenem after oral administration.展开更多
Indoxyl sulfate (IS) is a typical uremic toxin that extensively accumulates in the plasma of patients with seriously impaired renal function. This study seeks to clarify whether IS exerts a potent modulating effect on...Indoxyl sulfate (IS) is a typical uremic toxin that extensively accumulates in the plasma of patients with seriously impaired renal function. This study seeks to clarify whether IS exerts a potent modulating effect on the hepatic transport of pravastatin, which is a substrate of both organic anion transporting peptides (OATPs) and multidrug resistance-associated protein (Mrp) 2 in rats. When IS is administered intravenously to the normal rats at a dose of 120 μmol/kg;plasma IS levels are approximately 600 μM after 2 min and 100 μM after 120 min. In rats with acute renal failure (ARF) induced by cisplatin, the area under the curve (AUC) was more than 2.5-fold greater compared with that in the normal rats, indicating that IS accumulates in ARF rats. Intravenously administered pravastatin almost disappeared from the plasma by 60 min post-administration and approximately 55% of dose was excreted in the bile within 60 min. This result suggested that pravastatin was efficiently taken up from the sinusoid into hepatocytes via rat OATPs on the sinusoidal membrane and preferentially transported in the bile mediated by Mrp2 on the canalicular membrane. IS administered intravenously at a dose of 120 μmol/kg caused neither an increase in plasma pravastatin levels nor a decrease in its biliary excretion. In conclusion, the present results demonstrate that single intravenous administration of IS does not interfere with the hepatic transport of pravastatin directly in vivo, which is at variance with the results of previous in vitro studies.展开更多
文摘Meropenem, a carbapenem antibiotic, is inactive after oral administration and administered exclusively by injection. In this study, in order to address the factors involved in the oral inactivity of meropenem, in vitro permeation characteristics across rat ileal segments was investigated using diffusion cells. Moreover, stability of meropenem was evaluated in the Japanese Pharmacopoeia (JP) 1st and 2nd fluid for disintegration test. Cefotaxime, ceftibuten, and faropenem were used for comparison. The permeation of meropenem across rat ileal segments was approximately 5-fold greater in secretory direction than in absorptive direction. The secretory-oriented transport of meropenem markedly diminished by replacement of D-glucose in the experimental medium with unmetabolizing 3-O-methyl-D-glucose, suggesting that the secretory transport of meropenem was an energy-dependent process. Cefotaxime exhibited extensively secretory-oriented permeation. On the other hand, much weaker directionalities were observed in ceftibuten and faropenem. While meropenem as well as other three β-lactam antibiotics was stable in JP 2nd fluid (pH 6.8), it declined rapidly in JP 1st fluid (pH 1.2). These results suggest that, in addition to the hydrophilic property of meropenem, its instability at gastric pH and secretory transport in the small intestine are possible factors involved in the inactivity of meropenem after oral administration.
文摘Indoxyl sulfate (IS) is a typical uremic toxin that extensively accumulates in the plasma of patients with seriously impaired renal function. This study seeks to clarify whether IS exerts a potent modulating effect on the hepatic transport of pravastatin, which is a substrate of both organic anion transporting peptides (OATPs) and multidrug resistance-associated protein (Mrp) 2 in rats. When IS is administered intravenously to the normal rats at a dose of 120 μmol/kg;plasma IS levels are approximately 600 μM after 2 min and 100 μM after 120 min. In rats with acute renal failure (ARF) induced by cisplatin, the area under the curve (AUC) was more than 2.5-fold greater compared with that in the normal rats, indicating that IS accumulates in ARF rats. Intravenously administered pravastatin almost disappeared from the plasma by 60 min post-administration and approximately 55% of dose was excreted in the bile within 60 min. This result suggested that pravastatin was efficiently taken up from the sinusoid into hepatocytes via rat OATPs on the sinusoidal membrane and preferentially transported in the bile mediated by Mrp2 on the canalicular membrane. IS administered intravenously at a dose of 120 μmol/kg caused neither an increase in plasma pravastatin levels nor a decrease in its biliary excretion. In conclusion, the present results demonstrate that single intravenous administration of IS does not interfere with the hepatic transport of pravastatin directly in vivo, which is at variance with the results of previous in vitro studies.
