Pharmacokinetics of the Oral Direct Renin Inhibitor Aliskiren in Combination With Digoxin, Atorvastatin, and Ketoconazole in Healthy Subjects: The Role of P‐Glycoprotein in the Disposition of Aliskiren

Vaidyanathan, Sujata; Camenisch, Gian; Schuetz, Helmut; Reynolds, Christine; Yeh, Ching-Ming; Bizot, Marie-Noelle; Dieterich, H. A.; Howard, David L.; Dole, William P.

doi:10.1177/0091270008323258

Cited by 92 publications

(88 citation statements)

References 47 publications

(100 reference statements)

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“…Regardless, the estimated maximal gastrointestinal concentration of silymarin is significantly greater than the IC 50 for OATP2B1 inhibition, which could result in lower bioavailability of OATP2B1 substrates when administered orally with silymarin. Although drugs that are predominately absorbed by an OATP2B1-mediated process have yet to be identified, current drugs that may be partly dependent on OATP2B1-mediated transport include aliskiren, montelukast, and glibenclamide (Vaidyanathan et al, 2008;Mougey et al, 2009Mougey et al, , 2011Tapaninen et al, 2011). Recently, scutallarin, an active flavonoid in Erigheron brevisacapus extract was demonstrated to be a specific substrate for OATP2B1 (Gao et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

et al. 2013

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Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/ day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1-and OATP1B3-mediated estradiol-17b-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC 50 values of 1.3, 2.2 and 0.3 mM, respectively), silybin A (IC 50 values of 9.7, 2.7 and 4.5 mM, respectively), silybin B (IC 50 values of 8.5, 5.0 and 0.8 mM, respectively), and silychristin (IC 50 values of 9.0, 36.4, and 3.6 mM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 mM) significantly inhibited OATP-mediated estradiol-17b-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC 50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients.

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Section: Discussionmentioning

confidence: 99%

Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

et al. 2013

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“…Recently, grapefruit juice was found to reduce markedly the peak plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of the renininhibiting antihypertensive drug aliskiren [25]. Aliskiren is a substrate of OATP2B1, P-glycoprotein and CYP3A4 [26,27], and the mechanism of this interaction may be inhibition of the OATP2B1-mediated influx of aliskiren in the small intestine by grapefruit juice. Aliskiren is a hydrophilic, poorly absorbed compound with a low oral bioavailability (2-3%) [26,28,29].…”

Section: Introductionmentioning

confidence: 99%

Orange and apple juice greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren

Tapaninen

Neuvonen

Niemi

2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Aliskiren is an antihypertensive drug with a low oral bioavailability.• Aliskiren is eliminated primarily unchanged into bile, and it is a substrate of the organic anion transporting polypeptide 2B1 (OATP2B1) influx transporter, the P‐glycoprotein efflux transporter and cytochrome P450 3A4.• Flavonoids in orange and apple juice have been shown to inhibit OATP2B1 in vitro.WHAT THIS STUDY ADDS• Orange juice and apple juice markedly reduce the plasma concentrations of aliskiren probably by inhibiting its OATP2B1‐mediated intestinal absorption.• Concomitant intake of aliskiren with orange or apple juice is best avoided.AIM The aim of this study was to investigate the effects of orange juice and apple juice on the pharmacokinetics and pharmacodynamics of aliskiren.METHODS In a randomized crossover study, 12 healthy volunteers ingested 200 ml of orange juice, apple juice or water three times daily for 5 days. On day 3, they ingested a single 150‐mg dose of aliskiren. Plasma aliskiren concentrations were measured up to 72 h, its excretion into urine up to 12 h and plasma renin activity up to 24 h.RESULTS Orange and apple juice reduced aliskiren peak plasma concentrations by 80% (95% CI 63%, 89%, P < 0.001) and 84% (95% CI 72%, 91%, P < 0.001), and the area under the plasma aliskiren concentration–time curve (AUC) by 62% (95% CI 47%, 72%, P < 0.001) and 63% (95% CI 46%, 74%, P < 0.001), respectively, but had no significant effect on its elimination half‐life or renal clearance. The decreases in aliskiren AUC by orange and apple juice correlated with aliskiren AUC during the water phase (r= 0.98, P < 0.001). Plasma renin activity was 87% and 67% higher at 24 h after aliskiren during the orange juice and apple juice phases, respectively, than during the water phase (P < 0.05).CONCLUSIONS Orange juice and apple juice greatly reduce the plasma concentrations and renin‐inhibiting effect of aliskiren, probably by inhibiting its OATP2B1‐mediated influx in the small intestine. Concomitant intake of aliskiren with orange or apple juice is best avoided.

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“…Several statin drugs are known substrates of OATP2B1, including atorvastatin (18), rosuvastatin (19), and fluvastatin (20): these drugs can interact with other substrates, such as aliskiren (21), amiodarone (22), and glibenclamide (23), in the clinical setting and likely involve an interaction with OATP1B1 and/or OATP2B1 in the liver. The transporter-related study data can improve the patient safety and efficacy by selecting the optimum drug(s)/dose/ regimen for patients who are taking medications known to be OATP substrates, such as statins or anti-HIV drugs.…”

mentioning

confidence: 99%

Characterization of 22 Antituberculosis Drugs for Inhibitory Interaction Potential on Organic Anionic Transporter Polypeptide (OATP)-Mediated Uptake

Parvez

Jung

Shin

et al. 2016

Antimicrob Agents Chemother

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Pharmacokinetics of the Oral Direct Renin Inhibitor Aliskiren in Combination With Digoxin, Atorvastatin, and Ketoconazole in Healthy Subjects: The Role of P‐Glycoprotein in the Disposition of Aliskiren

Cited by 92 publications

References 47 publications

Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

Orange and apple juice greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren

Characterization of 22 Antituberculosis Drugs for Inhibitory Interaction Potential on Organic Anionic Transporter Polypeptide (OATP)-Mediated Uptake

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