Na(+)-independent multispecific anion transporter mediates active transport of pravastatin into rat liver

Yamazaki, Masayo; Suzuki, Hiroshi; Hanano, Manabu; Tokui, Taro; Komai, Takashi; Sugiyama, Yuichi

doi:10.1152/ajpgi.1993.264.1.g36

Cited by 102 publications

(96 citation statements)

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“…Nowadays, 3 kinds of organic anion transporters have been demonstrated in human liver cells [7]; among them, organic anion transporter type-2 (OATP-2) has been noted to be involved in the uptake of many drugs into liver cells. Similar transporters to this OATP-2 were confirmed in the rat liver, OATP-1/4 (3,17). It has been reported that endogenous reduced folate [8], PV [9,18] and methotrexate [11] are the substrate of these transporters.…”

Section: Discussionsupporting

confidence: 69%

Possible Active Transport Mechanism in Pharmacokinetics of Flunixin-Meglumin in Rabbits.

et al. 2001

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ABSTRACT. The plasma and urine kinetics of flunixin-meglumin (FNX, 2 mg/kg, i.v.) in rabbits were examined. Unusual pharmacokinetic profiles were obtained, including high binding percentage with plasma protein (> 99%), a short elimination half-life (< 4 hr) and a relatively large Vd-area (0.5 L/kg). These profiles indicate that some active transport mechanisms are involved in FNX disposition. The recovery of FNX from urine was approximately 9 % of the dose within 24 hr following the injection. The estimated renal clearance of the unbound drug nearly corresponded to the renal blood flow rates, indicating that active tubular secretion in the renal re-absorptive tract may be involved in the disposition. The effect of a concomitant administration of pravastatin (PV) on FNX disposition was also examined. PV is a representative substrate of a transporter in human liver cells (OATP-2). After the PV administrations, the Vd-area of FNX and total body clearance markedly decreased, indicating that FNX is actively taken up and metabolized in liver cells by an OATP-2 like transporter. In conclusion, there are at least 2 active transport pathways for FNX pharmacokinetics in rabbits, one is renal tubular secretion and the other is in the sinusoidal section of the liver.

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Section: Discussionsupporting

confidence: 69%

Possible Active Transport Mechanism in Pharmacokinetics of Flunixin-Meglumin in Rabbits.

et al. 2001

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“…Pravastatin is a hydrophilic molecule and is selectively taken up by hepatocytes via Na -independent multispecific anion transporters and energy-dependent transporters 22) , thereby having a direct effect on the liver. It has also been reported that pravastatin, but not other hydrophobic statins, can exert beneficial effects on some phenotypes of hepatocytes 23,24) .…”

Section: Discussionmentioning

confidence: 99%

Pravastatin Potentiates Increases in Serum Adiponectin Concentration in Dyslipidemic Patients Receiving Thiazolidinedione: the DOLPHIN Study

Nezu

Tsunoda

Yoshimura

et al. 2010

JAT

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Aim: A reduced risk of type 2 diabetes has been reported following treatment with pravastatin. Adiponectin is an adipocyte-derived protein that has an antidiabetic property. The objective of this study was to evaluate the effect of pravastatin on serum adiponectin concentration and other influencing factors. Methods: This study was a multicenter observational study: Dyslipidemia Open-labeled observational study by Lipid-lowering therapy with Pravastatin of the effect on High-molecular weight adiponectin in Nippon Yokohama (DOLPHIN). The protocol was registered in the UMIN Clinical Trial Registry as UMIN000000791. All patients received pravastatin 10 mg/day for 6 months and the change in concentration of total and high molecular weight adiponectin was assessed before and after follow-up. The difference in the change in total adiponectin concentration by patient characteristics was analyzed by an unpaired t-test. Influences of continuous variable factors on the change in total adiponectin concentration were estimated by simple linear regression analyses. Finally, in order to estimate the influences of factors that potentially affect the change in total adiponectin concentration induced by pravastatin, multiple linear regression analysis was conducted. Results: After 6 months, total adiponectin concentration was increased significantly by 23.2% from 11.7 6.4 to 13.7 8.6 g/mL (p 0.002). The use of thiazolidinedione as a concomitant medication was the only significant influencing factor ( 0.580, p 0.001). Conclusion: Pravastatin increased the serum adiponectin concentration in Japanese dyslipidemic patients without previous coronary artery disease. Interestingly, this effect was seen synergistically in combination with thiazolidinedione.

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“…Pravastatin is the most hydrophilic statin among the statins now in use and inhibits cholesterol biosynthesis selectively in hepatocytes 49) , while simvastatin, a hydrophobic statin, inhibits HMG-CoA reductase in all organs [46][47][48][49] . It has been reported that the relatively selective inhibition of hepatic cholesterol synthesis by hydrophilic pravastatin in vivo might be due to the existence of a specific uptake mechanism mediated by the Na( )-independent multispecific anion transporter system in the liver 50,51) .…”

Section: Discussionmentioning

confidence: 99%

Influence of 3-hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors on Ubiquinone Levels in Rat Skeletal Muscle and Heart: Relationship to Cytotoxicity and Inhibitory Activity for Cholesterol Synthesis in Human Skeletal Muscle Cells

Yamazaki¹,

Suzuki²,

Aoki³

et al. 2006

J Atheroscler Thromb

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Although statins are prescribed as relatively safe and effective drugs for hypercholesterolemic patients, it has been reported that a significant side effect, myopathy, occurs infrequently during medication. Moreover, because statins decrease cardiac ubiquinone levels, the risk of cardiac dysfunction has been suggested. This study sought to evaluate and compare the cytotoxicity of statins (cerivastatin, pitavastatin, fluvastatin, simvastatin, atorvastatin and pravastatin) in cultured human skeletal muscle cells (HSkMCs) and the effects on ubiquinone levels in statin-treated rat skeletal muscle and heart. Cerivastatin, the most potent inhibitor of HMG-CoA reductase, showed the strongest cytotoxicity (over 10-fold) among the statins examined, while the effects of the others were in a similar range. In rat experiments, neither pitavastatin nor cerivastatin decreased ubiquinone levels in skeletal muscle, but both dose-dependently lowered ubiquinone levels in the heart. As the rates of reduction by pitavastatin (9.6% at 30 mg/kg) and cerivastatin (9.7% at 0.3 mg/kg) were almost equal, it was estimated that cerivastatin reduced ubiquinone levels in the rat heart approximately 100-fold more strongly than pitavastatin, based on the effective doses. We found that cerivastatin showed the most potent cytotoxicity in HSkMCs and strongly lowered ubiquinone levels in the rat heart. J Atheroscler Thromb, 2006; 13:295-307.

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Na(+)-independent multispecific anion transporter mediates active transport of pravastatin into rat liver

Cited by 102 publications

References 0 publications

Possible Active Transport Mechanism in Pharmacokinetics of Flunixin-Meglumin in Rabbits.

Possible Active Transport Mechanism in Pharmacokinetics of Flunixin-Meglumin in Rabbits.

Pravastatin Potentiates Increases in Serum Adiponectin Concentration in Dyslipidemic Patients Receiving Thiazolidinedione: the DOLPHIN Study

Influence of 3-hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors on Ubiquinone Levels in Rat Skeletal Muscle and Heart: Relationship to Cytotoxicity and Inhibitory Activity for Cholesterol Synthesis in Human Skeletal Muscle Cells

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