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

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.

• Authors: Dan Xu, Feng Li, Mian Zhang, Ji Zhang, Can Liu, Meng-yue Hu, Ze-yu Zhong, Ling-ling Jia, Da-wei Wang, Jie Wu, Li Liu, Xiao-dong Liu
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 35 Issue 9 Pg. 1215-25 (Sep 2014) ISSN: 1745-7254 [Electronic] United States
• PMID: 25152023 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Abcc2 protein, rat
• Abcg2 protein, rat
• Organic Anion Transporters
• Slco1a4 protein, rat
• simvastatin acid
• Simvastatin
• Cytochrome P-450 CYP3A

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (metabolism)
• Animals
• Cytochrome P-450 CYP3A (metabolism)
• Diabetes Mellitus, Experimental (blood, metabolism)
• Diabetes Mellitus, Type 2 (blood, metabolism)
• Hepatocytes (metabolism)
• Liver (metabolism)
• Male
• Microsomes, Liver (metabolism)
• Organic Anion Transporters (metabolism)
• Rats
• Rats, Sprague-Dawley
• Simvastatin (analogs & derivatives, blood, pharmacokinetics)