In STZ-diabetic rats, the distribution volume of morphine increased, the glucuronidation rate and M3G transportation into the blood were enhanced, and the excretion of M3G was decreased, leading to an increase in the plasma M3G concentration.

In recent years, morbidity of diabetes, which is a metabolic disorder caused by the absence of insulin and/or organ response to this lack of insulin, has been increasing. Diabetes, hyperlipidemia, and hypertension accelerate arteriosclerosis and increase risk of stroke and heart disease. The major cause of diabetes, hyperlipidemia, and hypertension is obesity. The combination of those 4 factors (the obesity syndrome, diabetes, hypertension, and hyperlipidemia) is a risky condition called "the deadly quartet." The combination of diabetes and hyperlipidemia is especially dangerous because it promotes the development of atherosclerosis. Therefore, it is important for diabetic patients to control blood fat. Drugs such as 3-hydroxy-3-methylglutaryl enzyme A (HMG-CoA) reductase inhibitors (statins) are frequently administered to diabetic patients for this reason.Pravastatin, a hydrophilic statin, has a high safety profile and is often used for treating hyperlipemia in diabetic patients. However, serious symptoms like a rhabdomyolysis may be caused by pravastatin administration as the side effect.In diabetes, the expression of metabolic enzymes and transporters in the liver is altered. Shimojo demonstrated that the expressions of cytochrome P450 (CYP) 1A2, 2B1, and 4A were altered in rat models of type 1 diabetes induced by streptozotocin (STZ) treatment.1) Furthermore, van Waarde et al. reported that the expression of multidrug resistanceassociated protein 2 (MRP2) was decreased, whereas the expression of multidrug resistance-2 (MDR2) was increased, and that of the bile salt export pump (BSEP) was unchanged.2) It is possible that alterations of metabolic enzymes and transporters in the diabetic liver may change the disposition of pravastatin. The alteration of pravastatin disposition may lead to the decline or increase of the effect and the risk of the side effect. However, the disposition of pravastatin in diabetes has not been fully investigated. We consider that it is important to examine the change of pravastatin disposition in the diabetes for appropriate treatment of diabetic patients with pravastatin.Therefore, in the present study, we investigated the disposition of pravastatin in a rat model of streptozotocin-induced diabetes. Moreover, we also evaluated the changes in the mRNA expression of organic anion transporting polypeptide 2 (OATP2) and MRP2 in the liver and discussed these changes with regard to pravastatin disposition changes. MATERIALS AND METHODS MaterialsPravastatin and triamcinolone acetonide were purchased from Wako Pure Chemical Industries Ltd., Tokyo, Japan. STZ and Sepasol RNA I Super were obtained from Nacalai Tesque Inc., Kyoto, Japan. Glycogen solution and the SuperScript III first-strand synthesis system for reverse transcriptase-polymerase chain reaction (RT-PCR) were obtained from Life Technologies Inc., Tokyo, Japan. The KOD Dash kit was obtained from Toyobo Inc., Osaka, Japan. Sense and antisense primers for OATP2, MRP2, and b-actin were purchased from Bex Inc., Tokyo, Japan. All the ...

Objectives The aim of the study was to clarify the effect of insulin treatment on drug metabolism and disposition. Methods 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. Key findings 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. Conclusions 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.