Physiologically based pharmacokinetics of digoxin in mdr1a knockout mice

Kawahara, Masami; Sakata, Atsushi; Miyashita, Toshiaki; Tamai, Ikumi; Tsuji, Akira

doi:10.1021/js9901763

Cited by 97 publications

(75 citation statements)

References 24 publications

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“…To further investigate the effect of P-gp pharmacokinetics, especially the effect on plasma concentrations and brain penetration of sorafenib, studies in mdr1a/1b knockout mice were performed. The model was validated using [ 3 H]digoxin, a well characterized P-gp substrate (Mayer et al, 1996;Kawahara et al, 1999). The observed increase of radioactivity in plasma and brain of KO mice compared with WT mice is in good accordance with earlier publications reporting a 27-and 2.9-fold increase in brain and plasma concentrations, respectively (Schinkel et al, 1994(Schinkel et al, , 1997.…”

Section: Discussionsupporting

confidence: 87%

In Vitro to In Vivo Comparison of the Substrate Characteristics of Sorafenib Tosylate toward P-Glycoprotein

Gnoth¹,

Sandmann²,

Engel³

et al. 2010

Drug Metabolism and Disposition

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ABSTRACT:Sorafenib (Nexavar) is a novel oral Raf kinase and vascular endothelial growth factor receptor inhibitor. Most anticancer drugs are substrates for ATP-binding cassette efflux pumps especially for P-glycoprotein (P-gp). To evaluate the influence of P-gp on the pharmacokinetics of sorafenib substrate properties for this transporter were investigated. Therefore, permeability of sorafenib across Caco-2 and P-gp-overexpressing cells was determined. To determine the in vivo relevance of these in vitro findings, pharmacokinetics of sorafenib in mdr1a/1b(؊/؊) and wild-type (WT) mice was studied. Sorafenib is highly permeable and exhibits a slight efflux across Caco-2 cells. In P-gp-overexpressing cells, a small concentration-dependent efflux was observed, which was completely blocked by the addition of ivermectin. In mdr1a/1b(؊/؊) and WT mice, unchanged compound represented by far the majority of radioactivity in plasma. After intravenous and oral administration, brain/plasma concentration ratios in mdr1a/1b(؊/؊) mice were 1.3-to 1.5-fold higher than those in WT mice. However, after intravenous or oral administration, plasma concentrations were similar in both mouse strains. In conclusion, sorafenib is highly permeable and a weak P-gp substrate in vitro. These findings were confirmed by the small factor of 1.3 to 1.5 observed for the brain/plasma ratios in mdr1a/1b(؊/؊) versus WT mice in vivo. Based on these in vitro and in vivo results, it is unlikely that P-gp has a major effect on the plasma concentrations of sorafenib in humans. Because of the high permeability and low P-gp-mediated transport, sorafenib might be able to cross the blood-brain barrier and target tumors within the brain.

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Section: Discussionsupporting

confidence: 87%

In Vitro to In Vivo Comparison of the Substrate Characteristics of Sorafenib Tosylate toward P-Glycoprotein

Gnoth¹,

Sandmann²,

Engel³

et al. 2010

Drug Metabolism and Disposition

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“…This drug is commonly used to evaluate P-gp function in mice because the pharmacokinetic attributes of digoxin are highly P-gp dependent. Additionally, another advantage of using digoxin is that it is not significantly metabolized in mice (Schinkel et al, 1995Mayer et al, 1997;Kawahara et al, 1999). Although it is possible that digoxin is transported by other transporters (Taub et al, 2011), our observation was that calorie-restricted Abcb1a/b-null mice did not have decreased plasma concentration or increased digoxin content in intestine compared with ad libitum Abcb1a/b-null mice.…”

Section: Discussionmentioning

confidence: 70%

Calorie Restriction Increases P-Glycoprotein and Decreases Intestinal Absorption of Digoxin in Mice

Renaud

Klaassen

Csanaky

2016

Drug Metabolism and Disposition

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There is wide variation in how patients respond to therapeutics. Factors that contribute to pharmacokinetic variations include disease, genetics, drugs, age, and diet. The purpose of this study was to determine the effect of calorie restriction on the expression of Abcb1a in the intestine and whether calorie restriction can alter the absorption of an Abcb1a substrate (i.e., digoxin) in mice. Ten-week-old C57BL/6 mice were given either an ad libitum diet or a 25% calorie-restricted diet for 3 weeks. To determine digoxin absorption, mice were administered [ 3 H]-labeled digoxin by oral gavage. Blood and intestine with contents were collected at 1, 2, 4, and 12 hours after digoxin administration. Concentrations of [ 3 H]-digoxin in plasma and tissues were determined by liquid scintillation. Calorie restriction decreased plasma digoxin concentrations (about 60%) at 1, 2, and 4 hours after administration. Additionally, digoxin concentrations in the small intestine of calorie-restricted mice were elevated at 4 and 12 hours after administration. Furthermore, calorie restriction increased Abcb1a transcripts in the duodenum (4.5-fold) and jejunum (12.5-fold). To confirm a role of Abcb1a in the altered digoxin pharmacokinetics induced by calorie restriction, the experiment was repeated in Abcb1a/ b-null mice 4 hours after drug administration. No difference in intestine or plasma digoxin concentrations were observed between ad libitumfed and calorie-restricted Abcb1a/b-null mice. Thus, these findings support the hypothesis that calorie restriction increases intestinal Abcb1a expression, leading to decreased absorption of digoxin in mice. Because Abcb1a transports a wide variety of therapeutics, these results may be of important clinical significance.

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“…When digoxin is coadministrated with Pgp inhibitor (5,6), serum digoxin level is increased by reduction of renal excretion (2). In addition, decreased renal elimination of digoxin is also reported in Pgp knockout mouse (29). Thus, Pgp has an important role in the renal secretion of digoxin in the apical membrane.…”

Section: Discussionmentioning

confidence: 99%

Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney

Mikkaichi

Suzuki

Onogawa

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

259

242

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Digoxin, which is one of the most commonly prescribed drugs for the treatment of heart failure, is mainly eliminated from the circulation by the kidney. P-glycoprotein is well characterized as a digoxin pump at the apical membrane of the nephron. However, little is known about the transport mechanism at the basolateral membrane. We have isolated an organic anion transporter (OATP4C1) from human kidney. Human OATP4C1 is the first member of the organic anion transporting polypeptide (OATP) family expressed in human kidney. The isolated cDNA encodes a polypeptide of 724 aa with 12 transmembrane domains. The genomic organization consists of 13 exons located on chromosome 5q21. Its rat counterpart, Oatp4c1, is also isolated from rat kidney. Human OATP4C1 transports cardiac glycosides (digoxin, K m ‫؍‬ 7.8 M and ouabain, K m ‫؍‬ 0.38 M), thyroid hormone (triiodothyronine, Km ‫؍‬ 5.9 M and thyroxine), cAMP, and methotrexate in a sodiumindependent manner. Rat Oatp4c1 also transports digoxin (K m ‫؍‬ 8.0 M) and triiodothyronine (Km ‫؍‬ 1.9 M). Immunohistochemical analysis reveals that rat Oatp4c1 protein is localized at the basolateral membrane of the proximal tubule cell in the kidney. These data suggest that human OATP4C1͞rat Oatp4c1 might be a first step of the transport pathway of digoxin and various compounds into urine in the kidney.

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Physiologically based pharmacokinetics of digoxin in mdr1a knockout mice

Cited by 97 publications

References 24 publications

In Vitro to In Vivo Comparison of the Substrate Characteristics of Sorafenib Tosylate toward P-Glycoprotein

In Vitro to In Vivo Comparison of the Substrate Characteristics of Sorafenib Tosylate toward P-Glycoprotein

Calorie Restriction Increases P-Glycoprotein and Decreases Intestinal Absorption of Digoxin in Mice

Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney

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