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Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes.

Xu D, Li F, Zhang M, Zhang J, Liu C, Hu MY, Zhong ZY, Jia LL, Wang DW, Wu J, Liu L, Liu XD - Acta Pharmacol. Sin. (2014)

Bottom Line: The aim of the study was to investigate the pharmacokinetics of simvastatin and its hydrolysate simvastatin acid in a rat model of type 2 diabetes.The expression of Cyp3a1, organic anion transporting polypeptide 2 (Oatp2), multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) in livers was measured using qRT-PCR.Diabetes enhances the metabolism of simvastatin and simvastatin acid in rats via up-regulating hepatic Cyp3a activity and expression and increasing hepatic uptake.

View Article: PubMed Central - PubMed

Affiliation: 1] Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China [2] Jiangsu Provincial Institute of Traditional Chinese Medicine, Nanjing 210028, China.

ABSTRACT

Aim: Simvastatin is frequently administered to diabetic patients with hypercholesterolemia. The aim of the study was to investigate the pharmacokinetics of simvastatin and its hydrolysate simvastatin acid in a rat model of type 2 diabetes.

Methods: Diabetes was induced in 4-week-old rats by a treatment of high-fat diet combined with streptozotocin. After the rats received a single dose of simvastatin (20 mg/kg, po, or 2 mg/kg, iv), the plasma concentrations of simvastatin and simvastatin acid were determined. Simvastatin metabolism and cytochrome P4503A (Cyp3a) activity were assessed in hepatic microsomes, and its uptake was studied in freshly isolated hepatocytes. The expression of Cyp3a1, organic anion transporting polypeptide 2 (Oatp2), multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) in livers was measured using qRT-PCR.

Results: After oral or intravenous administration, the plasma concentrations and areas under concentrations of simvastatin and simvastatin acid were markedly decreased in diabetic rats. Both simvastatin metabolism and Cyp3a activity were markedly increased in hepatocytes of diabetic rats, accompanied by increased expression of hepatic Cyp3a1 mRNA. Furthermore, the uptake of simvastatin by hepatocytes of diabetic rats was markedly increased, which was associated with increased expression of the influx transporter Oatp2, and decreased expression of the efflux transporters Mrp2 and Bcrp.

Conclusion: Diabetes enhances the metabolism of simvastatin and simvastatin acid in rats via up-regulating hepatic Cyp3a activity and expression and increasing hepatic uptake.

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Related in: MedlinePlus

Simvastatin depletion in rat hepatic microsomes (A), 1-hydroxymidazolam formation from midazolam in rat hepatic microsomes (B) and the corresponding Eadie-Hofstee plots (C), and uptake of simvastatin (D) by hepatocytes of CON rats (open cycle), HFD rats (open triangle) and DM rats (solid cycle). Data were expressed as mean±SD of 3–4 rats. bP<0.05, cP<0.01 vs CON rats. eP<0.05, fP<0.01 vs HFD rats.
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fig3: Simvastatin depletion in rat hepatic microsomes (A), 1-hydroxymidazolam formation from midazolam in rat hepatic microsomes (B) and the corresponding Eadie-Hofstee plots (C), and uptake of simvastatin (D) by hepatocytes of CON rats (open cycle), HFD rats (open triangle) and DM rats (solid cycle). Data were expressed as mean±SD of 3–4 rats. bP<0.05, cP<0.01 vs CON rats. eP<0.05, fP<0.01 vs HFD rats.

Mentions: Simvastatin is primarily eliminated in the liver via metabolism. To investigate whether the alteration in the pharmacokinetics of simvastatin was derived from the enhancement of simvastatin metabolism in the liver of DM rats, the metabolism of simvastatin in hepatic microsomes of CON, HFD and DM rats was measured (Figure 3A) using a simple in vitro substrate depletion, and clearances in hepatic microsomes of CON, HFD and DM rats were estimated (Table 4). The results demonstrated that simvastatin metabolism was markedly (P<0.05) enhanced in hepatic microsomes of DM rats, leading to a significant (P<0.05) increase in simvastatin clearance (1.22-fold of CON rats). The HFD rats also showed a trend toward increasing clearance in hepatic microsomes; however, no significance was obtained.


Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes.

Xu D, Li F, Zhang M, Zhang J, Liu C, Hu MY, Zhong ZY, Jia LL, Wang DW, Wu J, Liu L, Liu XD - Acta Pharmacol. Sin. (2014)

Simvastatin depletion in rat hepatic microsomes (A), 1-hydroxymidazolam formation from midazolam in rat hepatic microsomes (B) and the corresponding Eadie-Hofstee plots (C), and uptake of simvastatin (D) by hepatocytes of CON rats (open cycle), HFD rats (open triangle) and DM rats (solid cycle). Data were expressed as mean±SD of 3–4 rats. bP<0.05, cP<0.01 vs CON rats. eP<0.05, fP<0.01 vs HFD rats.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4155525&req=5

fig3: Simvastatin depletion in rat hepatic microsomes (A), 1-hydroxymidazolam formation from midazolam in rat hepatic microsomes (B) and the corresponding Eadie-Hofstee plots (C), and uptake of simvastatin (D) by hepatocytes of CON rats (open cycle), HFD rats (open triangle) and DM rats (solid cycle). Data were expressed as mean±SD of 3–4 rats. bP<0.05, cP<0.01 vs CON rats. eP<0.05, fP<0.01 vs HFD rats.
Mentions: Simvastatin is primarily eliminated in the liver via metabolism. To investigate whether the alteration in the pharmacokinetics of simvastatin was derived from the enhancement of simvastatin metabolism in the liver of DM rats, the metabolism of simvastatin in hepatic microsomes of CON, HFD and DM rats was measured (Figure 3A) using a simple in vitro substrate depletion, and clearances in hepatic microsomes of CON, HFD and DM rats were estimated (Table 4). The results demonstrated that simvastatin metabolism was markedly (P<0.05) enhanced in hepatic microsomes of DM rats, leading to a significant (P<0.05) increase in simvastatin clearance (1.22-fold of CON rats). The HFD rats also showed a trend toward increasing clearance in hepatic microsomes; however, no significance was obtained.

Bottom Line: The aim of the study was to investigate the pharmacokinetics of simvastatin and its hydrolysate simvastatin acid in a rat model of type 2 diabetes.The expression of Cyp3a1, organic anion transporting polypeptide 2 (Oatp2), multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) in livers was measured using qRT-PCR.Diabetes enhances the metabolism of simvastatin and simvastatin acid in rats via up-regulating hepatic Cyp3a activity and expression and increasing hepatic uptake.

View Article: PubMed Central - PubMed

Affiliation: 1] Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China [2] Jiangsu Provincial Institute of Traditional Chinese Medicine, Nanjing 210028, China.

ABSTRACT

Aim: Simvastatin is frequently administered to diabetic patients with hypercholesterolemia. The aim of the study was to investigate the pharmacokinetics of simvastatin and its hydrolysate simvastatin acid in a rat model of type 2 diabetes.

Methods: Diabetes was induced in 4-week-old rats by a treatment of high-fat diet combined with streptozotocin. After the rats received a single dose of simvastatin (20 mg/kg, po, or 2 mg/kg, iv), the plasma concentrations of simvastatin and simvastatin acid were determined. Simvastatin metabolism and cytochrome P4503A (Cyp3a) activity were assessed in hepatic microsomes, and its uptake was studied in freshly isolated hepatocytes. The expression of Cyp3a1, organic anion transporting polypeptide 2 (Oatp2), multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) in livers was measured using qRT-PCR.

Results: After oral or intravenous administration, the plasma concentrations and areas under concentrations of simvastatin and simvastatin acid were markedly decreased in diabetic rats. Both simvastatin metabolism and Cyp3a activity were markedly increased in hepatocytes of diabetic rats, accompanied by increased expression of hepatic Cyp3a1 mRNA. Furthermore, the uptake of simvastatin by hepatocytes of diabetic rats was markedly increased, which was associated with increased expression of the influx transporter Oatp2, and decreased expression of the efflux transporters Mrp2 and Bcrp.

Conclusion: Diabetes enhances the metabolism of simvastatin and simvastatin acid in rats via up-regulating hepatic Cyp3a activity and expression and increasing hepatic uptake.

Show MeSH
Related in: MedlinePlus