Carrier-mediated uptake of pravastatin by rat hepatocytes in primary culture

Komai, Takashi; Shigehara, Eiji; Tokui, Taro; Koga, Tetsufumi; Ishigami, Michi; Kuroiwa, Chitose; Horiuchi, Seikoh

doi:10.1016/0006-2952(92)90228-b

Cited by 66 publications

(33 citation statements)

References 6 publications

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“…However, the number of silver grains in the spleen following administration of pravastatin was much less than that of simvastatin, and this differs from previous findings . Transport of pravastatin to hepatocytes is proposed to occur mainly via a Na ϩ -independent anion transporter in the sinusoidal membrane, due to the negative charge and hydrophilicity of pravastatin (Komai et al, 1992;Yamazaki et al, 1993). In contrast, passive diffusion may contribute largely to the transport of simvastatin because of its high lipophilicity (Komai et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…Transport of pravastatin to hepatocytes is proposed to occur mainly via a Na ϩ -independent anion transporter in the sinusoidal membrane, due to the negative charge and hydrophilicity of pravastatin (Komai et al, 1992;Yamazaki et al, 1993). In contrast, passive diffusion may contribute largely to the transport of simvastatin because of its high lipophilicity (Komai et al, 1992). Therefore, pravastatin might be distributed less than simvastatin to tissues/organs without that putative transport mechanism (e.g., the spleen).…”

Section: Discussionmentioning

confidence: 99%

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Liver-Specific Distribution of Rosuvastatin in Rats: Comparison with Pravastatin and Simvastatin

Nezasa¹,

Higaki²,

Matsumura³

et al. 2002

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Rosuvastatin is a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. The liver is the target organ for the lipid-regulating effect of rosuvastatin; therefore liver-selective uptake of this drug is a desirable property. The aim of this study was to investigate, and compare with pravastatin and simvastatin, the tissuespecific distribution of rosuvastatin. Bolus intravenous doses (5 mg/kg) of radiolabeled rosuvastatin, pravastatin, and simvastatin were administered to rats, and initial uptake clearance (CL uptake ) in various tissues was calculated. Hepatic CL uptake of rosuvastatin (0.885 ml/min/g tissue) was significantly (p < 0.001) larger than that of pravastatin (0.703 ml/min/g tissue), and rosuvastatin was taken up by the hepatic cells more selectively and efficiently than pravastatin. Hepatic CL uptake of simvastatin (1.24 ml/min/g tissue) was significantly larger than that of rosuvastatin (p < 0.01) and pravastatin (p < 0.001). However, adrenal CL uptake of simvastatin (1.55 ml/min/g tissue) was larger than hepatic CL uptake , and simvastatin was distributed to other tissues more easily than rosuvastatin. Microautoradiography of the liver, spleen, and adrenal was undertaken 5 min after administration of the study drugs; distribution was quantified by counting the number of silver grains. After administration of rosuvastatin and pravastatin, silver grains were distributed selectively in the intracellular space of the liver, but more rosuvastatin (3.3 ؎ 1.0 ؋ 10 5 particles/mm 2 ) than pravastatin (2.0 ؎ 0.3 ؋ 10 5 particles/mm 2 ) tended to distribute to the liver.Simvastatin was less liver-specific (it also distributed to the spleen and adrenal). The results of this study indicated that rosuvastatin was taken up by hepatic cells more selectively and more efficiently than pravastatin and simvastatin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Liver-Specific Distribution of Rosuvastatin in Rats: Comparison with Pravastatin and Simvastatin

Nezasa¹,

Higaki²,

Matsumura³

et al. 2002

Drug Metab Dispos

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“…Primary hepatocytes, plated or in suspension, as well as cell lines overexpressing individual transporters, are widely used to assess active hepatic uptake processes (Komai et al, 1992;Ismair et al, 2001;Shitara et al, 2003;Ho et al, 2006;Poirier et al, 2007). Nevertheless these cellular systems represent only one component of the dynamic and interlinked processes occurring in liver tissue.…”

mentioning

confidence: 99%

“…In hepatocytes, passive processes are typically assessed in a parallel incubation at 4°C to disable any active transport proteins (Komai et al, 1992;Ismair et al, 2001;Shimada et al, 2003;Lancon et al, 2004;Treiber et al, 2004;Ho et al, 2006). However, whereas active transport is inhibited at low temperature, passive processes might also be altered as membrane fluidity decreases (Frezard and GarnierSuillerot, 1998;Neuhoff et al, 2005;Webborn et al, 2007).…”

mentioning

confidence: 99%

Design, Data Analysis, and Simulation of in Vitro Drug Transport Kinetic Experiments Using a Mechanistic in Vitro Model

Poirier

Lavé²,

Portmann³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The use of in vitro data for quantitative predictions of transportermediated elimination in vivo requires an accurate estimation of the transporter Michaelis-Menten parameters, V max and K m , as a first step. Therefore, the experimental conditions of in vitro studies used to assess hepatic uptake transport were optimized regarding active transport processes, nonspecific binding, and passive diffusion (P dif ). A mechanistic model was developed to analyze and accurately describe these active and passive processes. This twocompartmental model was parameterized to account for nonspecific binding, bidirectional passive diffusion, and active uptake processes based on the physiology of the cells. The model was used to estimate kinetic parameters of in vitro transport data from organic anion-transporting peptide model substrates (e.g., cholecystokinin octapeptide deltorphin II, fexofenadine, and pitavastatin). Data analysis by this mechanistic model significantly improved the accuracy and precision in all derived parameters [mean coefficient of variations (CVs) for V max and K m were 19 and 23%, respectively] compared with the conventional kinetic method of transport data analysis (mean CVs were 58 and 115%, respectively, using this method). Furthermore, permeability was found to be highly temperature-dependent in Chinese hamster ovary (CHO) control cells and artificial membranes (parallel artificial membrane permeability assay). Whereas for some compounds (taurocholate, estrone-3-sulfate, and propranolol) the effect was moderate (1.5-6-fold higher permeability at 37°C compared with that at 4°C), for fexofenadine a 16-fold higher passive permeability was seen at 37°C. Therefore, P dif was better predicted if it was evaluated under the same experimental conditions as V max and K m , i.e., in a single incubation of CHO overexpressed cells or rat hepatocytes at 37°C, instead of a parallel control evaluation at 4°C.

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“…Pravastatin and paroxetine uptake and paroxetine metabolism in hepatocytes Primary rat hepatocytes were isolated according to a technique described previously [33,34] . The isolated hepatocytes, suspended in DMEM plating media supplemented with 5% (v/v) fetal bovine serum, 1 μmol/L dexamethasone, 4 μg/mL insulin, 50 U/mL penicillin and 0.05 mg/mL streptomycin, were seeded in 24-well plates at a density of 1×10 5 cells/well in 500 μL.…”

Section: Metabolism Of Paroxetine In Hepatic Microsomesmentioning

confidence: 99%

Co-administration of paroxetine and pravastatin causes deregulation of glucose homeostasis in diabetic rats via enhanced paroxetine exposure

Zhang

et al. 2014

Acta Pharmacol Sin

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Aim: Clinical evidence shows that co-administration of pravastatin and paroxetine deregulates glucose homeostasis in diabetic patients. The aim of this study was to verify this phenomenon in diabetic rats and to elucidate the underlying mechanisms. Methods: Diabetes mellitus was induced in male SD rats by a high-fat diet combined with a low-dose streptozotocin injection. The rats were orally administered paroxetine (10 mg/kg) and pravastatin (10 mg/d) or both the drugs daily for 28 d. The pharmacokinetics of paroxetine and pravastatin were examined on d 1 and d 28. Biochemical parameters including serum insulin, glucose and lipids were monitored during the treatments. An insulin-secreting cell line (INS-1) was used for measuring insulin secretion. Results: In diabetic rats, co-administration of paroxetine and pravastatin markedly increased the concentrations of both the drugs compared with administration of each drug alone. Furthermore, co-administration severely impaired glucose homeostasis in diabetic rats, as demonstrated by significantly increased serum glucose level, decreased serum and pancreatic insulin levels, and decreased pancreatic Insulin-2 mRNA and tryptophan hydroxylase-1 (Tph-1) mRNA levels. Treatment of INS-1 cells with paroxetine (5 and 10 μmol/L) significantly inhibited insulin secretion, decreased the intracellular insulin, 5-HT, Insulin-2 mRNA and Tph-1 mRNA levels. Treatment of the cells with pravastatin (10 μmol/L) significantly stimulated insulin secretion, which was weakened by co-treatment with paroxetine. Conclusion: Paroxetine inhibits insulin secretion at least via decreasing intracellular 5-HT and insulin biosynthesis. The deregulation of glucose homeostasis by co-administration of paroxetine and pravastatin in diabetic rats can be attributed to enhanced paroxetine exposure.

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Carrier-mediated uptake of pravastatin by rat hepatocytes in primary culture

Cited by 66 publications

References 6 publications

Liver-Specific Distribution of Rosuvastatin in Rats: Comparison with Pravastatin and Simvastatin

Liver-Specific Distribution of Rosuvastatin in Rats: Comparison with Pravastatin and Simvastatin

Design, Data Analysis, and Simulation of in Vitro Drug Transport Kinetic Experiments Using a Mechanistic in Vitro Model

Co-administration of paroxetine and pravastatin causes deregulation of glucose homeostasis in diabetic rats via enhanced paroxetine exposure

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