Clinical Pharmacokinetic Significance of the Renal Tubular Secretion of Digoxin

Koren, Gideon

doi:10.2165/00003088-198713050-00004

Cited by 35 publications

(27 citation statements)

References 41 publications

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“…Because digoxin secretion system is reported to be different from OAT and OCT systems (2,26), these data further suggest that other type(s) of molecule(s) should be involved in the basolateral transport of digoxin.…”

Section: Discussionmentioning

confidence: 82%

“…The OAT and OCT families transport relatively small hydrophilic ionic compounds at the basolateral membrane of the proximal tubule. However, the OAT and OCT families do not transport uncharged and charged hydrophobic compounds such as digoxin and thyroid hormone (2,26). Tubular secretion of digoxin seems to be a major route of eliminating into urine (2).…”

Section: Discussionmentioning

confidence: 99%

“…However, the OAT and OCT families do not transport uncharged and charged hydrophobic compounds such as digoxin and thyroid hormone (2,26). Tubular secretion of digoxin seems to be a major route of eliminating into urine (2). In the past, glomerular filtration was considered as a main elimination pathway because digoxin excretion is correlated with glomerular filtration rate.…”

Section: Discussionmentioning

confidence: 99%

“…Because digoxin is mainly eliminated to the urine (2) and it is difficult to control the serum digoxin level in renal failure, it is important to clarify the mechanism of renal tubular handling. The kidney has the essential role for elimination of various compounds from the circulation.…”

mentioning

confidence: 99%

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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.

257

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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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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.

257

242

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“…A competitive renal inhibition is unlikely as indomethacin and digoxin are secreted by different tubular sites (Koren, 1987). Inhibition of the prostaglandin synthesis by indomethacin might change the renal microcirculation influencing the elimination of digoxin, but no experimental studies, however, support this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Interaction between digoxin and indomethacin or ibuprofen.

Jørgensen

1991

Brit J Clinical Pharma

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To study a potential interaction between digoxin and two non‐steroid anti‐inflammatory drugs, indomethacin (50 mg three times daily) and ibuprofen (600 mg three times daily) were given for 10 days to 10 and 8 patients, respectively, on chronic digoxin treatment. Serum digoxin measured by fluorescence polarisation immunoassay increased significantly (P less than 0.05) during treatment with indomethacin from pre‐treatment values of 0.73 +/− 0.34 nmol l‐1 (mean +/− s.d.) to a mean value of 1.02 +/− 0.43 nmol l‐1, while administration of ibuprofen did not change the steady state serum concentration of digoxin. The result demonstrates that some non‐steroidal anti‐ inflammatory drugs such as indomethacin increase serum digoxin to levels high in the therapeutic range. This should be taken into consideration when co‐administering other drugs known to increase the serum concentration of digoxin such as several antiarrhythmics.

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The Effects of Epoprostenol on Drug Disposition I: A Pilot Study of the Pharmacokinetics of Digoxin with and without Epoprostenol in Patients with Congestive Heart Failure

Carlton¹,

Patterson²,

Mattson³

et al. 1996

The Journal of Clinical Pharma

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The influence of epoprostenol on the pharmacokinetics of drugs administered concurrently to patients with congestive heart failure (CHF) receiving epoprostenol was evaluated as a secondary objective of a Phase II pilot study. A total of 278 blood samples were collected from 30 patients with end-stage CHF receiving conventional therapy alone or conventional therapy plus epoprostenol. Estimates of oral clearance (Cl), volume of distribution, and absorption rate constant of digoxin were generated from plasma digoxin concentrations using nonlinear mixed effects modeling, and the effect of epoprostenol on Cl of digoxin was evaluated by univariate analysis. Additional factors that were evaluated by univariate analysis included age, obesity, time since study entry, cardiac output, concomitant use of angiotensin-converting enzyme (ACE) inhibitor, concomitant dobutamine, and estimated creatinine clearance. Backward elimination was used to arrive at a final model that included concomitant epoprostenol as a covariate. The final model revealed an approximate 15% decrease in Cl of digoxin in response to short-term administration of epoprostenol that was no longer apparent by the end of the 12-week treatment phase. Simulations revealed that this effect, although statistically significant, would not be clinically significant in most patients; however, the potential exists for short-term elevation of digoxin concentrations in response to concurrent administration of epoprostenol.

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Clinical Pharmacokinetic Significance of the Renal Tubular Secretion of Digoxin

Cited by 35 publications

References 41 publications

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

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

Interaction between digoxin and indomethacin or ibuprofen.

The Effects of Epoprostenol on Drug Disposition I: A Pilot Study of the Pharmacokinetics of Digoxin with and without Epoprostenol in Patients with Congestive Heart Failure

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