Decreased exposure of atorvastatin in diabetic rats partly due to induction of hepatic Cyp3a and Oatp2

Abstract

1. Atorvastatin is frequently prescribed for lowering blood cholesterol and for prevention of events associated with cardiovascular disease. The aim of this study was to investigate the pharmacokinetics of atorvastatin in diabetic rats. 2. Diabetes was induced in rats by combination of high-fat diet and low-dose streptozotocin (35 mg/kg). Plasma concentrations of atorvastatin following oral (10 mg/kg) and intravenous (2 mg/kg) administrations to rats were measured by LC-MS. Metabolism and uptake of atorvastatin in primary hepatocytes of experimental rats were assessed. Protein expressions and activities of hepatic Cyp3a and Oatp2 were further investigated. 3. Clearances of atorvastatin in diabetic rats following oral and intravenous administrations were remarkably increased, leading to marked decreases in area-under-the-plasma concentration-time curve (AUC). The estimated oral and systematic clearances of atorvastatin in diabetic rats were 4.5-fold and 2.0-fold of control rats, respectively. Metabolism and uptake of atorvastatin in primary hepatocytes isolated from diabetic rats were significantly increased, which were consistent with the up-regulated protein expressions and activities of hepatic Cyp3a and Oatp2. 4. All these results demonstrated that the plasma exposure of atorvastatin was significantly decreased in diabetic rats, which was partly due to the up-regulated activities and expressions of both hepatic Cyp3a and Oatp2.

Imbalance of Drug Transporter-CYP450s Interplay by Diabetes and Its Clinical Significance

“…The transporter-enzyme interplay also occurs in the intestine and kidney. Accumulating studies [9][10][11][12] have demonstrated that diabetes remarkably alters the expression and functions of drug transporters and CYP450s, disordering transporter-CYP450 interplay and in turning affecting the disposition of corresponding drugs, their therapeutic efficacy or drug toxicity.…”

“…OATPs, expressed at the basolateral membrane of hepatocytes, mediates hepatocyte uptake of many anions from the blood, which becomes a rate-limited process of hepatic clearances for some drugs [3]. It was found that in diabetic rats (type 2 diabetes) induced by a streptozocin (STZ) and high-fat diet (HFD) combination (termed as STZ/HFD), hepatic OATP1B2 (rodent orthologue of human OATP1B1 and OATP1B3) is remarkably induced, leading to increased hepatic uptake of repaglinide [9,10], atorvastatin [9,11] and simvastatin [12] as well as hepatic clearances [9,11]. In line with this, the diabetic rats showed lower plasma concentrations of atorvastatin [9,11], simvastatin [12] and pravastatin [13] compared with control rats.…”

“…It was found that in diabetic rats (type 2 diabetes) induced by a streptozocin (STZ) and high-fat diet (HFD) combination (termed as STZ/HFD), hepatic OATP1B2 (rodent orthologue of human OATP1B1 and OATP1B3) is remarkably induced, leading to increased hepatic uptake of repaglinide [9,10], atorvastatin [9,11] and simvastatin [12] as well as hepatic clearances [9,11]. In line with this, the diabetic rats showed lower plasma concentrations of atorvastatin [9,11], simvastatin [12] and pravastatin [13] compared with control rats. Clinical trials also showed that tuberculosis patients with diabetes showed significantly lower concentrations of rifampicin than non-diabetic patients [14,15], which may be attributed to the induction of hepatic OATPs by diabetes and rifampicin.…”

“…Growing evidence has demonstrated that diabetes increases the expression of some CYP450s (such as CYP2A1, CYP1A2, CYP2B1/2, CYP2C6, CYP2C7, CYP3A1/2 and CYP2E1) in rats [9,11,12,[26][27][28][29][30], although opposite reports have also been shown [31,32]. The induction of CYP3A1/2 led to lower plasma exposure of simvastatin [12], atorvastatin [9,11], verapamil [27,29] and lidocaine [30] following intravenous dose to diabetic rats. The formation of 1,3-dimethyluric acid from theophylline is mainly mediated via CYP1A2 and CYP2E1.…”

“…The transporter-enzyme interplay also occurs in the intestine and kidney. Accumulating studies [9][10][11][12] have demonstrated that diabetes remarkably alters the expression and functions of drug transporters and CYP450s, disordering transporter-CYP450 interplay and in turning affecting the disposition of corresponding drugs, their therapeutic efficacy or drug toxicity. Here, we aimed to focus on (1) the imbalance of transporter-CYP450 interplay in the liver, intestine and kidney due to alterations in the expression of influx transporters, efflux transporters and CYP450s under diabetic status; (2) the net contributions of the altered expressions and functions of transporters and CYP450s to drug disposition, therapeutic efficacy and drug toxicity; (3) application of a physiologically based pharmacokinetic model (PBPK) in the imbalance of transporter-enzyme interplay under diabetic conditions.…”