Pharmacokinetics of pravastatin in heart-transplant patients taking cyclosporin A*

Park, J W; Siekmeier, R.; Merz, Mechthild; Krell, B; Harder, Sebastian; März, Winfried; Seidel, D.; Schüler, Stephan; Gross, W

doi:10.5414/cpp40439

Cited by 54 publications

(49 citation statements)

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“…Therefore pravastatin, which presents a greater hydrophilicity, would have lower rates of passive diffusion [51]. This result confirmed previous studies showing that pravastatin was taken by a membrane transporter [14,52,53].…”

Section: Thermodynamic Parameterssupporting

confidence: 88%

“…Statins are a well-established class of drugs in the treatment of hypercholesterolemia, and have been shown to significantly reduce the risk of cardiovascular morbidity and mortality in the world [5,[9][10][11]. Indeed, many studies have been demonstrated the important place on statins in the treatment of hypercholesterolemia and many diseases like heart, renal transplantations, atherosclerosis, Alzheimer [12][13][14]. Statins are classified according to their origin: fungal metabolites (natural statins) like mevastatin, simvastatin, pravastatin and synthetic statins like atorvastatin, fluvastatin [1].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Statins (HMG-coenzyme A reductase inhibitors)–biomimetic membrane binding mechanism investigated by molecular chromatography

Sarr

André

Guillaume

2008

Journal of Chromatography B

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Section: Thermodynamic Parameterssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Statins (HMG-coenzyme A reductase inhibitors)–biomimetic membrane binding mechanism investigated by molecular chromatography

Sarr

André

Guillaume

2008

Journal of Chromatography B

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“…Cyclosporine, for instance, inhibited OATP1B1-and OATP1B3-mediated drug uptake in vitro (Treiber et al, 2007). Thus, it has been observed in humans that coadministration of the OATP1B1 and OATP1B3 substrate pravastatin with cyclosporine increased the plasma concentrations of pravastatin (Regazzi et al, 1993;Olbricht et al, 1997;Park et al, 2002;Hedman et al, 2004). Because pravastatin is not metabolized to a significant extent (Jacobsen et al, 1999), inhibition of OATP1B1-and OATP1B3-mediated pravastatin uptake may be one relevant molecular mechanism behind this observed drug-drug interaction.…”

Section: Discussionmentioning

confidence: 99%

Influence of Non-Steroidal Anti-Inflammatory Drugs on Organic Anion Transporting Polypeptide (OATP) 1B1- and OATP1B3-Mediated Drug Transport

Kindla

Müller²,

Mieth³

et al. 2011

Drug Metab Dispos

100

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ABSTRACT:The transporter-mediated uptake of drugs from blood into hepatocytes is a prerequisite for intrahepatic drug action or intracellular drug metabolism before excretion. Therefore, uptake transporters, e.g., members of the organic anion transporting polypeptide (OATP) family are important determinants of drug pharmacokinetics. Highly and almost exclusively expressed in hepatocytes are the OATP family members OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3). Drug substrates of OATP1B1 and OATP1B3 include antibiotics and HMG-CoA reductase inhibitors (statins). It has been demonstrated that administration of two or more drugs that are substrates for these hepatic uptake transporters may lead to transporter-mediated drug-drug interactions, resulting in altered transport kinetics for drug substrates. In this study we investigated whether non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol interact with OATP1B1 and OATP1B3 using the standard substrate BSP and the drug substrate pravastatin. Using human embryonic kidney cells stably expressing OATP1B1 or OATP1B3, we demonstrated that bromosulfophthalein uptake was inhibited by diclofenac, ibuprofen. and lumiracoxib. Of interest, pravastatin uptake was stimulated by these NSAIDs, and for ibuprofen we determined activation constants (EC 50 values) of 64.0 and 93.1 M for OATP1B1-and OATP1B3-mediated uptake, respectively. Furthermore, we investigated whether NSAIDs were also substrates for OATP1B1 and OATP1B3 and demonstrated that only diclofenac was significantly transported by OATP1B3, whereas all other NSAIDs investigated were not substrates for these uptake transporters. These results demonstrated that drugs may interact with transport proteins by allosteric mechanisms without being substrates and, therefore, not only uptake inhibition but also allosteric-induced modulation of transport function may be an important mechanism in transporter-mediated drug-drug interactions.

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“…Nevertheless, a 5-to 23-fold increase in pravastatin bioavailability has been reported in the presence of cyclosporine A. 4,27 It has been postulated that competition for carrier-mediated transport across the bile canalicular membrane between pravastatin and cyclosporine leads to a reduced biliary clearance of pravastatin. 4 A cyclosporine-pravastatin interaction may occur also at the level of the transport protein P-glycoprotein.…”

Section: Statin Interactions With Cyp450 Inhibitorsmentioning

confidence: 99%

Safety of Statins

2004

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Abstract-Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Because statins are prescribed on a long-term basis, however, possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment.

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Pharmacokinetics of pravastatin in heart-transplant patients taking cyclosporin A*

Cited by 54 publications

References 0 publications

Statins (HMG-coenzyme A reductase inhibitors)–biomimetic membrane binding mechanism investigated by molecular chromatography

Statins (HMG-coenzyme A reductase inhibitors)–biomimetic membrane binding mechanism investigated by molecular chromatography

Influence of Non-Steroidal Anti-Inflammatory Drugs on Organic Anion Transporting Polypeptide (OATP) 1B1- and OATP1B3-Mediated Drug Transport

Safety of Statins

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