Effects of dexamethasone to reverse decreased hepatic midazolam metabolism in rats with acute renal failure.

The inductive effects of dexamethasone on hepatic midazolam metabolism were examined in Wistar rats with acute renal failure (ARF) to clarify whether the ARF-related decrease in the hepatic expression of drug-metabolizing enzymes is caused by an impairment in the translation/polypeptide formation process.ARF was induced with intramuscular glycerol injection. Dexamethasone was orally administered. Pooled liver microsomes from five rats were prepared with ultracentrifugation for each of four groups, namely, control and ARF rats, control rats with dexamethasone treatment and ARF rats with dexamethasone treatment.Hepatic drug-metabolizing activity was examined in an incubation study with the microsomes, where midazolam was employed as a substrate of cytochrome P450 (CYP) 3A enzymes. The hepatic protein and mRNA expressions of CYP3A23/3A1 and 3A2 enzymes were also evaluated.With dexamethasone treatment, the hepatic metabolic rate of midazolam increased 1.4 times in control rats, while it increased 19.6 times in ARF rats, reflecting the greater induction of hepatic protein expressions of CYP3A enzymes in ARF rats than in control rats.The hepatic protein expression process for CYP3A23/3A1 and 3A2 responds well to dexamethasone treatment in ARF rats, indicating that the translation/polypeptide formation process is not impaired in the presence of ARF.

Control of Nausea Based on Risk Analysis in Patients with Esophageal and Gastric Cancer Who Received Cisplatin-based Chemotherapy.

BACKGROUND: Cisplatin is commonly used for esophageal and gastric cancer, but has a high emetic risk. Although the control of vomiting is favorable, nausea is still poorly controlled in patients receiving cisplatin-based regimens. The present study was designed to determine the risks for cisplatin-induced nausea. The effect of olanzapine, an antipsychotic drug, as an antiemetic for patients with risk of poor control of nausea was subsequently examined. PATIENTS AND METHODS: The prevalence of antiemetic medication and the control of nausea and vomiting were retrospectively examined in patients with esophageal or gastric cancer receiving the first cycle of cisplatin-based chemotherapy. Risks for nausea were analyzed by multivariate logistic regression analysis, in which threshold for age and cisplatin dose wer assessed by receiver operating characteristic curve analysis. RESULTS: A total of 186 patients received cisplatin-based regimens during January 2011 and December 2016. Guideline-consistent antiemetic medication was administered to all patients. Although the rate of no vomiting was high (93%), the rate of non-significant (grade 2 or more) nausea was insufficient (64%) during the overall period. Risk analysis showed that cisplatin dose of 50 mg/m2 or more and female gender were significant risks for nausea. Addition of olanzapine, but not of prochlorperazine, to the standard antiemetic medication was effective in suppressing nausea in patients who experienced nausea in the first cycle. CONCLUSION: Being female and cisplatin doses at 50 mg/m2 or more were demonstrated to increase risk for nausea. Addition of olanzapine to the standard medication was effective in preventing nausea in high-risk patients with esophageal and gastric cancer.

Effect of carrageenan-induced acute peripheral inflammation on the pharmacokinetics and hepatic metabolism of midazolam in rats.

The effect of carrageenan-induced acute peripheral inflammation (API) on the pharmacokinetics of the hepatically metabolizing compound midazolam (MDZ) was investigated in rats. Rats were subcutaneously treated with λ-carrageenan in the hind paw to induce API. When MDZ was intravenously administered in male rats, it was demonstrated that the plasma concentration profile of MDZ slightly alters in API rats compared with that in normal rats, while the plasma concentrations of its metabolites, 4-hydroxy and 1'-hydroxy MDZ, are markedly reduced with delayed appearances in API rats. In the incubation study with rat liver microsomes, it was clearly indicated that the generation rates of the two metabolites decrease in API rats. Western blot analysis revealed that hepatic CYP3A1 expression increases, while CYP3A2 expression decreases in API rats. In female rats, in which CYP3A2 is barely expressed in the liver, MDZ metabolism is little affected by API. These findings indicate that the hepatic handling of a therapeutic compound varies with API, largely due to altered hepatic expression of the drug-metabolizing enzyme.

Comparative study on altered hepatic metabolism of CYP3A substrates in rats with glycerol-induced acute renal failure.

To examine the mechanism accounting for the diverse alteration of hepatic metabolism of CYP3A substrates observed with renal function being severely impaired, the hepatic drug metabolizing activity was evaluated using liver microsomes prepared from rats with glycerol-induced acute renal failure (ARF). Midazolam, nifedipine and rifabutin were employed as representative CYP3A substrates. When the Michaelis-Menten parameters, K(m) and V(max) , were examined in the incubation study, the K(m) values of midazolam and nifedipine in ARF rats were shown to decrease by 50.9% and 29.9% compared with the normal value, respectively. The V(max) values of midazolam and nifedipine in ARF rats also decreased by 49.3% and 28.0%, respectively, showing that their decreased K(m) values accompanied the decreased V(max) values. The parameters of nifedipine seemed to alter to a lesser extent than those of midazolam. As for rifabutin metabolism, the decrease in the K(m) value was observed in ARF rats, but it did not accompany the decrease in the V(max) value. Then, the hepatic expressions of the CYP3A subfamily were examined with western blotting using anti-CYP3A1 and anti-CYP3A2 antibodies. It was revealed that the hepatic expression of CYP3A2 decreased, while that of CYP3A1 was unaffected. Additionally, a band signal deduced to originate from CYP3A9 was clearly detected in ARF, but not in normal rats. Considering each substrate having different specificities for CYP3A subfamily member proteins, individual alterations of hepatic CYP3A subfamily expression seem to underlie the diverse alterations of hepatic metabolism of CYP3A substrates in ARF rats.