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Abstract
To characterise the dose-dependent pharmacokinetics of midazolam and evaluate the intestinal and hepatic first-pass effects on midazolam in Sprague-Dawley rats, the concentrations and area under the concentration-time curve (AUC) of midazolam in the portal and systemic plasma were simultaneously determined with a double cannulation method.
It was found that about 75% of the dose was left in the portal blood with different oral administration doses, while the bioavailability in the liver was 37.86% at 20 mg/kg, significantly higher than 9.16% at 2 mg/kg.
The disproportional increase in AUC of midazolam and significant decrease in exposure of metabolites were observed in systemic plasma after hepatic portal vein administration. And in the in vitro study, the formation rate of the metabolites of midazolam significantly decreased when midazolam was at 300 μM compared with 100 μM.
These results indicated that not only the saturation of first-pass metabolism but also the inhibition of hepatic metabolism is responsible for the nonlinear PK of midazolam. Thus, a rational dose should be chosen when midazolam is used as a probe in the drug-drug interaction study, particularly for orally administered drugs that undergo hepatic first-pass metabolism.
Ethical approval
The animal study was reviewed and approved by the Ethics Committee of China Pharmaceutical University (CPU-PK-202004009).
Authors’ contributions
RL and QQW performed the majority of the experiments and analysed the data; RL wrote the manuscript; ZHL, LKX, and ZPD supported several experiments; YP, GJW, and JGS supervised the research and revised the manuscript.
Disclosure statement
The authors report there are no competing interests to declare.