Dynamic and kinetic disposition of nisoldipine enantiomers in hypertensive patients presenting with type-2 diabetes mellitus

Marques, Maria Paula; Coelho, Eduardo Barbosa; Santos, Neife Aparecida Guinaim dos; Geleilete, Tufik José Magalhães; Lanchote, Vera Lúcia

doi:10.1007/s00228-002-0528-4

Cited by 43 publications

(52 citation statements)

References 27 publications

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“…The activity and expression of hepatic Cyp3a in DM rats were associated with HOMA-IR, which suggests that insulin resistance or relative insufficiency of insulin may explain the affecting expression and activity of hepatic Cyp3a. Several reports have demonstrated that insulin and ketone bodies participating in the regulation of cytochrome P450 isozymes in the liver of DM rats and insulin treatment reversed or partially reversed alteration induced by diabetes [17,[37][38][39] . The elevated total serum cholesterol and triglyceride levels in DM rats were consistent with the increases in activity and expression of hepatic Cyp3a, suggesting that high cholesterol and triglyceride levels may explain inducing Cyp3a expression and activity.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating reports have shown that diabetes alters the metabolism rates of drugs via affecting activities and expressions of CYP450s and drug transporter in the liver [15,17,20,35] . Simvastatin, a substrate of Cyp3 and Oatp2/OATP1B1, is often used for improving hypercholesterolemia associated with DM.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that OATP1B1 plays a clinically important role in the hepatic elimination of several drugs including statins, via mediating the hepatic uptake [11][12][13][14][15] . Both clinical trials and animal experiments have demonstrated that DM may alter the pharmacokinetic behaviors of some drugs via regulating the expressions and activities of cytochrome P450s (CYP450s) and drug transporters in the liver [16][17][18][19][20][21][22] . Breast cancer resistance protein (Bcrp) and multidrug resistance-associated protein 2 (Mrp2) have also been reported to mediate statin transport [11,23,24] .…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

et al. 2014

Acta Pharmacol Sin

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zhang

et al. 2014

Acta Pharmacol Sin

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“…Type 2 diabetes mellitus is a common health problem associated with cardiovascular disease, with an increasing incidence worldwide (Gomes et al, 2009), and hypertension is an extremely common co-morbid condition in diabetes, affecting more than 50% of patients with diabetes mellitus (Marques et al, 2002). In recent years, clinical trials have demonstrated the effectiveness of aggressive treatment of hypertension in reducing macrovascular and microvascular diabetes complications.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, a target blood pressure goal of lower than 130/80 mmHg is now recommended. It must be noted that many patients will require three or more drugs (Marques et al, 2002). Structures of nisoldipine including calcium antagonists of the dihydropyridine class, to achieve blood pressure control (American Diabetes Association, 2002).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Interaction between Nisoldipine and Repaglinide in Rats

Choi¹,

Choi²,

Yeum³

2011

Biomolecules and Therapeutics

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Abstractglinide has affi nity for P-gp and it can signifi cantly contribute to potential drug-drug interactions with other P-gp substrates or inhibitors (Chang et al., 2006). Kajosaari et al. reported that co-administration of repaglinide with the known P-gp inhibitor cyclosporine A could signifi cantly increase the plasma concentrations of repaglinide in humans (Kajosaari et al., 2005).Nisoldipine is a calcium antagonist of the 1,4-dihydropyridine class, it is often clinically used as an anti-angina and vasodilating agent (Chandler et al., 1992). Nisoldipine is well absorbed from the gastrointestinal tract after oral administration, but undergoes rapid and extensive fi rst-pass metabolism in the gut wall and liver (van Harten et al., 1989). Nisoldipine is mainly eliminated by metabolism. Oxidation of 1,4-dihydropyridine (nisoldipine) to pyridine, catalysed by CYP3A4, is the major metabolic route (Guengerich et al., 1991). In general, the substrate and/or inhibitors of CYP3A4 and P-gp overlap with each other (Wacher et al., 1995), however, there are few reports about P-gp activity for nisoldipine. Therefore, we evaluated the P-gp activity of nisoldipine using rhodamine-123 retention assays in P-gp-overexpressing MCF-7/ADR cells. In order to verifi cation the inhibition of CYP enzyme activity, weOriginal Article

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Comparative pharmacokinetic study of paclitaxel and docetaxel in streptozotocin‐induced diabetic rats

Lee

et al. 2012

Biopharm & Drug Disp

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The pharmacokinetics of paclitaxel and docetaxel were compared in diabetic rats induced by streptozotocin (DMIS rats) and the impact of altered expression of cytochrome P450 3A (Cyp3A) and P-glycoprotein (P-gp) in the diabetic state. The pharmacokinetics of paclitaxel and docetaxel were determined after intravenous (5 mg/kg) and oral (30 and 40 mg/kg, respectively) administration to both groups and the mRNA expression levels of Cyp3A isozymes and Mdr1a and Mdr1b in the liver and small intestine were determined in control and DMIS rats. After intravenous administration, the AUC and clearance of paclitaxel and docetaxel were not significantly different in DMIS vs control rats. After oral administration, the AUC and C(max) of paclitaxel in DMIS rats were significantly greater than those in the control rats, whereas those of docetaxel was not changed significantly. The mRNA expression levels of hepatic Cyp3A1, Cyp3A9 and Mdr1b were significantly increased in DMIS compared with the control rats. In the intestine, Cyp3A62 expression decreased in the DMIS rats compared with the controls. Thus the pharmacokinetic changes of taxanes observed in the DMIS rats were attributed to changes in P-gp and Cyp3A, predominant factors that control the absorption of paclitaxel and docetaxel, respectively. It seemed that there were different susceptibilities to intestinal P-gp and Cyp3A between the two taxanes.

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Dynamic and kinetic disposition of nisoldipine enantiomers in hypertensive patients presenting with type-2 diabetes mellitus

Abstract: The present data permit us to infer that type-2 diabetes mellitus alters the kinetic disposition of the (+)-N eutomer and (-)-N distomer, presumably due to a lower activity of CYP3A4, although it does not modify the clinical effect brought about by the reduction in BP.

Cited by 43 publications

References 27 publications

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

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

Pharmacokinetic Interaction between Nisoldipine and Repaglinide in Rats

Comparative pharmacokinetic study of paclitaxel and docetaxel in streptozotocin‐induced diabetic rats

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