Laboratory of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.
J Pharm Pharmacol. 2010 Jul;62(7):883-9. doi: 10.1211/jpp.62.05.0009.
The aim of the study was to clarify the effect of insulin treatment on drug metabolism and disposition.
We investigated the mRNA expression and activity of cytochrome P450 (CYP) 3A, which is involved in the metabolism of several drugs, by using a rat model of diabetes and insulin-treated diabetes. In addition, we investigated the mRNA expression of the nuclear receptors reported to regulate the transcription of CYP3A, pregnane X receptor (PXR) and constitutive androstane receptor (CAR). We also assessed the disposition of nicardipine, which is mainly metabolised by CYP3A, using both rat models to evaluate the influence of insulin treatment on drug disposition.
We noted that alterations in the serum bile acid concentration in both rat groups were related to the changes in CAR mRNA expression, CYP3A mRNA expression and CYP3A activity. Furthermore, although the enhanced CYP3A activity in the diabetic rat accelerated the elimination of nicardipine, insulin administration decreased the enhanced CYP3A activity in the diabetic group and delayed the elimination of nicardipine to the same level as that in the control group. However, the steady-state volume of distribution was increased in the insulin-treated diabetic group as compared to the control and diabetic groups. We further noted that although the CYP3A activity in the diabetic group returned to the same level as in that in the non-diabetic group by insulin treatment, other values, such as the distribution volume of nicardipine, did not show a similar return.
Based on our results, we suggest that alterations in the drug disposition in diabetes and insulin-treated diabetes should be taken into consideration in order to provide safe and effective drug therapy.
本研究旨在阐明胰岛素治疗对药物代谢和处置的影响。
我们使用糖尿病大鼠模型和胰岛素治疗的糖尿病大鼠模型，研究了参与多种药物代谢的细胞色素 P450（CYP）3A 的 mRNA 表达和活性。此外，我们还研究了报道调节 CYP3A 转录的核受体——孕烷 X 受体（PXR）和组成型雄烷受体（CAR）的 mRNA 表达。我们还评估了尼卡地平的处置情况，尼卡地平主要通过 CYP3A 代谢，使用这两种大鼠模型来评估胰岛素治疗对药物处置的影响。
我们注意到两组大鼠血清胆汁酸浓度的变化与 CAR mRNA 表达、CYP3A mRNA 表达和 CYP3A 活性的变化有关。此外，尽管糖尿病大鼠中增强的 CYP3A 活性加速了尼卡地平的消除，但胰岛素给药降低了糖尿病组中增强的 CYP3A 活性，并将尼卡地平的消除延迟至与对照组相同的水平。然而，与对照组和糖尿病组相比，胰岛素治疗组的稳态分布容积增加。我们进一步注意到，尽管糖尿病组的 CYP3A 活性通过胰岛素治疗恢复到与非糖尿病组相同的水平，但其他值，如尼卡地平的分布容积，并没有表现出类似的恢复。
基于我们的结果，我们建议在糖尿病和胰岛素治疗的糖尿病中，应考虑药物处置的改变，以提供安全有效的药物治疗。
