Role of P-Glycoprotein Inhibition for Drug Interactions

Eberl, Sonja; Renner, Bertold; Neubert, Antje; Reisig, Mareike; Bachmakov, Iouri; König, Jörg; Dörje, Frank; Mürdter, Thomas E.; Ackermann, Andreas; Dormann, Harald; Gaßmann, K-G; Hahn, Eckhart G.; Zierhut, S.; Brune, Kay; Fromm, Martin F.

doi:10.2165/00003088-200746120-00004

Cited by 103 publications

(17 citation statements)

References 2 publications

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“…Indeed, azithromycin was strongly associated (odds ratio 3.71) with development of digoxin toxicity[9] in a population-based study. These findings were consistent with the earlier work of Eberl and colleagues,[10] who studied the inhibitory potential of macrolides (including azithromycin) in an in vitro model of P-glycoprotein-mediated digoxin transport using Caco-2 cells. This is especially important since similar to digoxin, simvastatin is a high-affinity substrate for multidrug efflux transporter P-glycoprotein, and efflux inhibition by azithromycin increases the risk of simvastatin toxicity by reducing energy-dependent simvastatin transport from enterocytes into the intestinal lumen (effectively increasing bioavailability).…”

Section: Discussionsupporting

confidence: 92%

Rhabdomyolysis caused by an unusual interaction between azithromycin and simvastatin

Alreja

Inayatullah

Goel

et al. 2012

Journal of Cardiovascular Disease Research

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Rhabdomyolysis is an uncommon but life-threatening adverse effect of simvastatin therapy. A 73-year-old male on chronic simvastatin therapy received azithromycin for acute bronchitis. He presented with weakness of all extremities with a significant increase in creatinine phosphokinase levels and acute kidney injury. Simvastatin was stopped and supportive therapy with intravenous saline and bicarbonate was initiated. The serum creatinine and creatine phosphokinase returned to baseline in the next 7 days. Two months later, simvastatin was resumed without any recurrence of symptoms. Our case report highlights the rare description of rhabdomyolysis caused by a drug interaction between simvastatin with azithromycin.

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Section: Discussionsupporting

confidence: 92%

Rhabdomyolysis caused by an unusual interaction between azithromycin and simvastatin

Alreja

Inayatullah

Goel

et al. 2012

Journal of Cardiovascular Disease Research

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“…demonstrated that the co-administration of the P-glycoprotein inhibitor erythromycin and cardiac glycosides (digoxin) in hospitalized patients was associated with increased serum concentration of the latter. [58] Wakasugi et al . had earlier shown that clarithromycin increased the plasma concentration of co-administered digoxin by inhibition of P-glycoprotein–mediated renal excretion.…”

Section: Adverse Effects Of Efflux Pump Inhibitorsmentioning

confidence: 99%

Efflux pump-mediated resistance in chemotherapy

Ughachukwu

Unekwe

2012

Ann Med Health Sci Res

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Efflux pump mechanisms perform important physiological functions such as prevention of toxin absorption from the gastrointestinal tract, elimination of bile from the hepatocytes, effective functioning of the blood–brain barrier and placental barrier, and renal excretion of drugs. They exist in all living cells, but those in the bacterial and mammalian cells are more important to the clinician and pharmacologist, as they constitute an important cause of antimicrobial drug resistance, which contributes to treatment failure, high medical bills, and increased mortality / morbidity. This review was aimed at highlighting the role of efflux pump mechanisms in microbial resistance to chemotherapeutic agents. It was also aimed to elucidate their structure and mechanisms of action so as to integrate the efflux pump mechanisms in the design and development of novel antimicrobial agents. Findings from previous studies and research on this subject assessed through Google search, Pubmed, Hinari websites, as well as standard textbooks on chemotherapy, provided the needed information in the process of this review. Efflux pump inhibitors are promising strategies for preventing and reverting efflux-mediated resistance to chemotherapeutic agents. They are usually employed as adjuncts in antimicrobial and cancer chemotherapy. Toxicity, more common with the older-generation inhibitors such as verapamil and reserpine, constitutes the greatest impediment to their clinical applications. No efflux pump inhibitor has been approved for routine clinical use, as a result of doubtful clinical efficacy and unacceptably high incidence of adverse effects, particularly inhibition of the P-450 drug metabolizing enzyme. At present, their applications are mainly restricted to epidemiological studies. Nonetheless, the search for efficacious and tolerable efflux pump inhibitors continues because of the potential benefits. There is a need to consider efflux pump substrate selectivity in the design and development of novel chemotherapeutic agents.

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“…Test chemical interaction with P-gp was measured by dividing NMQ concentrations for all test chemicals by those measured for DMSO to determine % P-gp transport activity. Verapamil and erythromycin, known inhibitors of P-gp, were used as controls (Eberl et al, 2007;Heredi-Szabo et al, 2013). Analyses of P-gp mediated transport of propiconazole (at 1 mM, 10 mM, and 100 mM final concentrations) in membrane vesicles was performed using the same protocol (as with NMQ) with the exception that reaction time varied (3-30 min).…”

Section: Bmentioning

confidence: 99%

P-glycoprotein inhibition by the agricultural pesticide propiconazole and its hydroxylated metabolites: Implications for pesticide–drug interactions

2015

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Role of P-Glycoprotein Inhibition for Drug Interactions

Abstract: Macrolides are potent inhibitors of P-glycoprotein. Drug interactions between P-glycoprotein inhibitors and substrates are likely to occur during hospitalisation.

Cited by 103 publications

References 2 publications

Rhabdomyolysis caused by an unusual interaction between azithromycin and simvastatin

Rhabdomyolysis caused by an unusual interaction between azithromycin and simvastatin

Efflux pump-mediated resistance in chemotherapy

P-glycoprotein inhibition by the agricultural pesticide propiconazole and its hydroxylated metabolites: Implications for pesticide–drug interactions

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