Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone

Ziegler, K.; Hummelsiep, Silke

doi:10.1016/0005-2736(93)90272-2

Cited by 23 publications

(25 citation statements)

References 36 publications

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“…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. Supposing that rabbits might also have a similar transporter in their liver, we examined the pharmacokinetics of FNX in rabbits using concomitant administration of a large amount of PV, expecting to block possible FNX uptake into the liver cells by means of PV.…”

Section: Discussionsupporting

confidence: 69%

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

Miyazaki

Horii

Ikenaga

et al. 2001

The Journal of Veterinary Medical Science

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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.

Miyazaki

Horii

Ikenaga

et al. 2001

The Journal of Veterinary Medical Science

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“…Total simvastatin concentrations in brain, liver, and serum correlated significantly whereas there was no such effect seen in pravastatin-treated animals. The different effects of simvastatin and pravastatin on cerebral and peripheral cholesterol synthesis may in part be due to the differences in metabolism and lipophilicity, as well as the different uptake and tissue selectivity (Ziegler and Hummelsiep, 1993;van Vliet et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Brain Cholesterol Synthesis in Mice Is Affected by High Dose of Simvastatin but Not of Pravastatin

Thelen

Rentsch

Gutteck

et al. 2005

J Pharmacol Exp Ther

135

122

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On a global scale, there is an increasing tendency for a more aggressive treatment of hypercholesterolemia. Minor effects of statins on brain cholesterol metabolism have been reported in some in vivo animal studies, and it seems that this is due to a local effect of the drug. We treated male mice of the inbred strain C57/BL6 with a high daily dose of lipophilic simvastatin (100 mg/kg b.wt.) or hydrophilic pravastatin (200 mg/kg b.wt.) or vehicle (controls) by oral gavage for 3 days. To compare the impact of both statins on brain cholesterol synthesis and degradation, levels of cholesterol, its precursor lathosterol, and its brain metabolite 24(S)-hydroxycholesterol as well as statin concentrations were determined in whole-brain lipid extracts using mass spectrometry. The expression of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase mRNA and of other target genes were evaluated using real-time reverse transcription-polymerase chain reaction. In addition, analysis of liver and serum samples was performed. Similar levels of simvastatin and pravastatin were detected in whole-brain homogenates. Cholesterol contents in the brain, liver, and serum were not affected by high-dose statin treatment. Whereas brain cholesterol precursor levels were reduced in simvastatin-treated animals only, no effect was observed on the formation of the brain cholesterol metabolite, 24(S)-hydroxycholesterol. Polymerase chain reaction analysis revealed that mRNA expression of HMG-CoA reductase and ATP-binding cassette transporter A1 in the brain was significantly up-regulated in simvastatintreated animals compared with pravastatin-treated or control animals. We conclude that, under the present experimental conditions, brain cholesterol synthesis is significantly affected by short-term treatment with high doses of lipophilic simvastatin, whereas whole-brain cholesterol turnover is not disturbed.

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“…Only in the hepatocyte can the peptide accumulate to such an extent that the cytoskeletal protein actin is blocked. OATP carriers transport bile acids (Trauner and Boyer 2003) and a plethora of drugs (Hagenbuch and Meier 2003) including HMG-CoA reductase inhibitors such as pravastatin (Ziegler and Stünkel 1992;Ziegler and Hummelsiep 1993;Hsiang et al 1999). Oatps were addressed by drugs conjugated with bile acids in a bile acid-based drug targeting approach for the liver (Kramer et al 1992;Meijer 1993;Petzinger et al 1995;Kramer and Wess 1996).…”

Section: Clinical Importance Of Implementing Drug Transporter Phasesmentioning

confidence: 99%

Drug transporters in pharmacokinetics

Petzinger¹,

Geyer²

2006

Naunyn Schmied Arch Pharmacol

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This review deals with the drug transporters allowing drugs to enter and leave cells by carrier-mediated pathways. Emphasis is put on liver transporters but systems in gut, kidney, and blood-brain barrier are mentioned as well. Drug-drug interactions on carriers may provoke significant modification in pharmacokinetics as do carrier gene polymorphisms yielding functional carrier protein mutations. An integrated phase concept should reflect the interplay between drug metabolism and drug transport.

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Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone

Cited by 23 publications

References 36 publications

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

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

Brain Cholesterol Synthesis in Mice Is Affected by High Dose of Simvastatin but Not of Pravastatin

Drug transporters in pharmacokinetics

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