Oral bioavailability of digoxin is enhanced by talinolol: Evidence for involvement of intestinal P-glycoprotein

Westphal, Kristin; Weinbrenner, Anita; Gießmann, Thomas; Stuhr, Marko; Franke, G; Zschiesche, M; Oertel, Reinhard; Terhaag, B; Kroemer, Heyo K.; Siegmund, Werner

doi:10.1067/mcp.2000.107579

Cited by 175 publications

(125 citation statements)

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“…The positive inotropic effects of digoxin exhibit a substantial inter-individual variability (Dobbs et al 1987), and cardiac P-gp may be one factor contributing to this effect. Moreover, several ␤ -blocking drugs have been described as P-gp substrates (e.g., talinolol, celiprolol; Karlsson et al 1993;Westphal et al 2000). Administration of ␤ -blockers in patients with heart failure has been established as standard therapy and, again, therapeutic effects show a wide inter-individual variability, which may in part be explained by expression of drug transporters in human heart.…”

Section: Discussionmentioning

confidence: 99%

“…Conventional RT-PCR was performed as described previously (Westphal et al 2000). PCR products for MDR1 mRNA (157 bp) and for glyceraldehyde 3-phosphate dehydrogenase (GAPDH; 110 bp) were separated on a 8% polyacrylamide gel, stained with VistraGreen (Amersham Pharmacia Biotech; Freiburg, Germany) and band intensities were analyzed using the Storm 840 Imager (Molecular Dynamics; Krefeld, Germany).…”

Section: Rt-pcr Analysis Of Mdr1mentioning

confidence: 99%

“…Digoxin has been unequivocally identified as a P-gp substrate by experiments in cell lines, in animals, and in humans (de Lannoy and Silverman 1992). The disposition of several ␤ -blocking drugs (e.g., talinolol, pafenolol) is modulated by P-gp (Westphal et al 2000). Moreover, cardiotoxic drugs such as anthracyclines (e.g., doxorubicin) are P-gp substrates (Fardel et al 1997) and accumulate in cardiac tissue of mdr Ϫ / Ϫ mice (van Asperen et al 1999).…”

mentioning

confidence: 99%

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Expression and Localization of P-glycoprotein in Human Heart

Meissner¹,

Sperker²,

Karsten³

et al. 2002

J Histochem Cytochem.

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S U M M A R Y ABC-type transport proteins, such as P-glycoprotein (P-gp), modify intracellular concentrations of many substrate compounds. They serve as functional barriers against entry of xenobiotics (e.g., in the gut or the blood-brain barrier) or contribute to drug excretion. Expression of transport proteins in the heart could be an important factor modifying cardiac concentrations of drugs known to be transported by P-gp (e.g., ␤ -blockers, cardiac glycosides, doxorubicin). We therefore investigated the expression and localization of P-gp in human heart. Samples from 15 human hearts (left ventricle; five non-failing, five dilated cardiomyopathy, and five ischemic cardiomyopathy) were analyzed for expression of P-gp using real-time RT-PCR, immunohistochemistry, and in situ hybridization. Immunohistochemistry revealed expression of P-gp in endothelium of both arterioles and capillaries of all heart samples. Although P-gp mRNA was detected in all samples, its expression level was significantly reduced in patients with dilated cardiomyopathy. We describe variable expression of P-gp in human heart and its localization in the endothelial wall. Thus, intracardiac concentrations of various compounds may be modified, depending on the individual P-gp level.

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Section: Discussionmentioning

confidence: 99%

Section: Rt-pcr Analysis Of Mdr1mentioning

confidence: 99%

mentioning

confidence: 99%

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Expression and Localization of P-glycoprotein in Human Heart

Meissner¹,

Sperker²,

Karsten³

et al. 2002

J Histochem Cytochem.

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“…Clinical drug-drug interactions were reported in the literature between digoxin (a good P-gp substrate) and other drugs, such as quinidine [97][98][99], verapamil [100 -102], talinolol [103], clarithromycin [104], itraconazole [105], erythromycin [106], and propafenone [101,107,108].…”

Section: Drug-drug Interactionsmentioning

confidence: 99%

Concise Review: Clinical Relevance of Drug–Drug and Herb–Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein)

et al. 2007

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Key Words. P-glycoprotein • Drug interaction • Complementary and alternative medicine • CAM • Pharmacokinetics Pharmacodynamics LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Identify important sources of variability in drug exposure caused by drug interactions mediated by P-glycoprotein.2. Describe how unwanted drug-drug interactions may lead to unexpected serious toxicity or undertreatment.3. Prevent these interactions by individualizing pharmacotherapy; this means selecting noninteracting drugs or adapting the dose of (the) interacting drug(s).Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTThe importance of P-glycoprotein (P-gp) in drug-drug interactions is increasingly being identified. P-gp has been reported to affect the pharmacokinetics of numerous structurally and pharmacologically diverse substrate drugs. Furthermore, genetic variability in the multidrug resistance 1 gene influences absorption and tissue distribution of drugs transported. Inhibition or induction of P-gp by coadministered drugs or food as well as herbal constituents may result in pharmacokinetic interactions leading to unexpected toxicities or undertreatment. On the other hand, modulation of P-gp expression and/or activity may be a useful strategy to improve the pharmacological profile of anticancer P-gp substrate drugs. In recent years, the use of complementary and alternative medicine (CAM), like herbs, food, and vitamins, by cancer patients has increased significantly. CAM use substantially increases the risk for interactions with anticancer drugs, especially because of the narrow therapeutic window of these compounds. However, for most CAMs, it is unknown whether they affect metabolizing enzymes and/or drug transporter activity. Clinically relevant interactions are reported between St John's wort or grapefruit juice and anticancer as well as nonanticancer drugs. CAM-drug interactions could explain, at least in part, the large interindividual variation in efficacy and toxicity associated with drug therapy in both cancer and noncancer patients.

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“…Modulators of P-gp have been reported to affect the bioavailability of digoxin in humans [19,20] and to inhibit its renal clearance in vitro [16]. Solifenacin is a weak inhibitor of P-gp (IC 50 = 5.1 µ M ) [21], and therefore we have investigated the potential effect of solifenacin on the steady-state pharmacokinetics of digoxin and the tolerability of solifenacin and digoxin administered concomitantly.…”

Section: Introductionmentioning

confidence: 99%

Multiple doses of the antimuscarinic agent solifenacin do not affect the pharmacodynamics or pharmacokinetics of warfarin or the steady‐state pharmacokinetics of digoxin in healthy subjects

Smulders

Kuipers

Krauwinkel

2006

Brit J Clinical Pharma

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AimsSolifenacin succinate is used for the treatment of overactive bladder (OAB). The potential for pharmacokinetic and/or pharmacodynamic interactions between solifenacin and warfarin or digoxin was investigated. MethodsThe solifenacin-warfarin study was a two-period crossover trial conducted in healthy males. Subjects received warfarin on the 10th day of 16 days of dosing with either solifenacin or placebo. The solifenacin-digoxin study was an one-sequence crossover trial conducted in healthy males and females. Following a phase-in period for digoxin, solifenacin was administered concomitantly with the drug on days 9-18. ResultsThe AUC PT; 0 − 168 h following a single dose of warfarin was unchanged in the presence of solifenacin [point estimate = 1.005; 90% confidence interval (CI) 0.98, 1.02)]. The AUC 0-∞ values for both warfarin enantiomers were also unchanged. A small increase in the C max of digoxin was observed during treatment with solifenacin, but for AUC ss,tau and C max the 90% CI fell within the prespecified interval of 0.80-1.25. Combined administration of solifenacin and warfarin or digoxin was well tolerated. ConclusionsSince the pharmacokinetics and pharmacodynamics of a single dose of war farin and the steady-state pharmacokinetics of digoxin were not affected by coadministration of solifenacin in healthy subjects, the need for dosing adjustments for digoxin and/ or warfarin does not seem warranted.

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Oral bioavailability of digoxin is enhanced by talinolol: Evidence for involvement of intestinal P-glycoprotein

Abstract: We observed a significantly increased bioavailability of digoxin with oral coadministration of talinolol, which is most likely caused by competition for intestinal P-glycoprotein.

Cited by 175 publications

References 36 publications

Expression and Localization of P-glycoprotein in Human Heart

Expression and Localization of P-glycoprotein in Human Heart

Concise Review: Clinical Relevance of Drug–Drug and Herb–Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein)

Multiple doses of the antimuscarinic agent solifenacin do not affect the pharmacodynamics or pharmacokinetics of warfarin or the steady‐state pharmacokinetics of digoxin in healthy subjects

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