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

Abstract

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Keywords:

• Acute renal failure
• CYP3A2
• dexamethasone
• hepatic drug metabolism
• midazolam

Disclosure statement

The authors declare that there are no conflicts of interest. The authors take full responsibility for any unforeseen conflict of interest that may arise.

Additional information

Funding

This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Sciences [24590192/15K08097/19K07220].