<i>In Vivo</i> Study on Mechanism Underlying Increased Pharmacological Effects of Phenobarbital in Rats with Glycerol-Induced Acute Renal Failure

Abstract

The mechanism underlying the increased pharmacological effects of phenobarbital in rats with glycerolinduced acute renal failure (ARF) was examined. In the experiments, a surgical cannula was inserted in the lateral ventricle of the rats for phenobarbital infusion, and the ARF induction was performed by intramuscular administration of 50% glycerol. The onset time of anesthesia by phenobarbital was determined with the tail flick method. In addition, cerebral microsomes were prepared from excised cerebral cortices of sham and ARF rats, and the cerebral expression of the γ-aminobutyric acid (GABA) A receptor and two cation-chloride transporters, KCC2 and NKCC1, was evaluated by Western blotting, as their functions are involved in the anesthetic effects of phenobarbital. When phenobarbital was infused in the ventricle, anesthesia was induced 2.2-times faster in ARF rats than in sham rats, and there was no detectable increase in the cerebral expression of the GABA A receptor in ARF rats. It was additionally noted that the cerebral expression of KCC2 decreased, whereas that of NKCC1 was unaltered in ARF rats. These findings indicated that the anesthetic effects of phenobarbital are potentiated in ARF rats, probably due to imbalanced cerebral expression of KCC2 and NKCC1, suggesting that altered cation-chloride handling in nerve cells is associated.

Acute Peripheral Inflammation Increases Plasma Concentration of Hypoglycemic Agent Nateglinide with Decreased Hepatic Drug-Metabolizing Activity in Rats

“…Additionally, it was demonstrated that the NTG elimination is suppressed with sulfaphenazole applied at a higher concentration, while the elimination remains unaltered in the presence of ketoconazole (Table 3). Since sulfaphenazole has been reported to inhibit CYP2C11-mediated hepatic drug metabolism in a selective manner when applied at a concentration of 100 µM, 26) it is considered that NTG metabolism is mainly mediated by the CYP2C11 isozyme, and to a lesser degree by the CYP3A2 isozyme, in our incubation experiments. 28) Along with these findings and the understanding that the CYP2C11 isozyme is predominantly expressed among the CYP2C family in male rat liver, 29) we examined the hepatic expression of CYP2C11 protein, and observed that it appears to decrease in API rats (Fig.…”

“…These concentrations of the inhibitors were set to selectively inhibit the hepatic drug-metabolizing activity via CYP2C and 3A isoenzymes in rats. 26) The incubation experiments were carried out in the same manner as described above with the final concentration of NTG being set at 100 µM, and the β-NADPH-dependent elimination rates of NTG were evaluated. The elimination rates with and without the inhibitors were compared to examine whether the inhibitors affect the hepatic NTG elimination.…”

Altered Pharmacological Efficacy of Phenobarbital with the Treatment of 7,8-Dihydroxyflavone, an Agonist of Tropomyosin Receptor Kinase B, in Rats

“…The cannula insertion surgery was performed as reported previously. 16) Following anesthetization with sodium pentobarbital (80 mg/kg, intraperitoneally, each rat was fixed to a stereotaxic instrument (Narishige, Tokyo, Japan) and its skull surface was disinfected with 10% povidone iodine solution. Then, a hole of 1 mm in diameter was drilled in the skull to access the right lateral ventricle at the brain atlas coordinates of 0.0 mm anterior and 1.5 mm lateral from the bregma, with a close attention not to compromise the brain tissue.…”

“…In our previous study with intraventricular phenobarbital infusion, it was observed that phenobarbital induces general anesthesia with a smaller dose in rats when they are suffering from acute renal failure, showing that the pharmacological efficacy of phenobarbital is affected by impaired renal function. 15,16) These observations indicate that it is necessary to investigate and understand the mechanisms underlying the altered pharmacological efficacy of therapeutic compounds, especially in patients with severe diseases, because current optimization and individualization methods in pharmacotherapy do not consider alteration of the pharmacological efficacy of the compounds. Regarding the underlying mechanisms for the increased pharmacological efficacy of phenobarbital, it was also observed that the cerebral protein expression of the potassium chloride cotransporter KCC2 (SLC12A5) decreases, but there were no detectable alterations for the cerebral expression of the phenobarbital target site, or the γ-aminobutyric acid A (GABA A ) receptor, in rats with acute renal failure.…”

“…Regarding the underlying mechanisms for the increased pharmacological efficacy of phenobarbital, it was also observed that the cerebral protein expression of the potassium chloride cotransporter KCC2 (SLC12A5) decreases, but there were no detectable alterations for the cerebral expression of the phenobarbital target site, or the γ-aminobutyric acid A (GABA A ) receptor, in rats with acute renal failure. 16) Since KCC2 is an electrolyte transporter, mainly mediating chloride effluence in the nerve cells, 17,18) it is speculated that a decreased expression of the KCC2 protein may lead to altered electrolyte handling in the nerve cells, causing a suppression of the nerval action potential and transmission.…”