Effect of spironolactone on excretion of 3H-digoxin and its metabolites in rats

Wirth, K; Frölich, Jürgen C.

doi:10.1016/0014-2999(74)90168-x

Cited by 23 publications

(6 citation statements)

References 17 publications

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“…Most of the drug-metabolizing enzymes present in the liver are also found in the small intestine, despite the fact that the levels are generally much lower in the small intestine (Lin et al, 1999). Digoxin is metabolized in the rat (Wirth and Frölich, 1974;Harrison and Gibaldi, 1976;Salphati and Benet, 1999), with approximately 60% of the total body plasma clearance (5.77 ml/min) being attributed to biotransformation (Harrison and Gibaldi, 1976) by Cyp3a (Salphati and Benet, 1999). Hepatic metabolism (Salphati and Benet, 1999;Liu et al, 2005) must have accounted for most of the biotransformation since in vitro incubations of digoxin with rat intestinal tissue showed that digoxin was not metabolized by rat enterocytes to any significant extent (Sababi et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

P-Glycoprotein and an Unstirred Water Layer Barring Digoxin Absorption in the Vascularly Perfused Rat Small Intestine Preparation: Induction Studies with Pregnenolone-16α-carbonitrile

Liu¹,

Tam²,

Chen³

et al. 2006

Drug Metab Dispos

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Section: Discussionmentioning

confidence: 99%

P-Glycoprotein and an Unstirred Water Layer Barring Digoxin Absorption in the Vascularly Perfused Rat Small Intestine Preparation: Induction Studies with Pregnenolone-16α-carbonitrile

Liu¹,

Tam²,

Chen³

et al. 2006

Drug Metab Dispos

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“…Although there are the usual recognizable TABLE 6 The effects of zonal heterogeneity of influx/efflux transport, metabolism, and secretion on clearances in digoxin hepatic disposition: simulations with the PBPK zonal model (Fig. 4B) species differences between rat and man in terms of the transport and metabolism of digoxin in the liver (Doherty and Perkins, 1962;Wirth and Frolich, 1974), the poor hepatic clearance and metabolism, the red cell and albumin binding, and the high lipophilicity suggest a similar role of red cell and albumin binding on the hepatic clearance of digoxin in human. For the cumulative amount of Dg3 excreted into bile,…”

Section: Khb-perfused Liversmentioning

confidence: 99%

Vascular Binding, Blood Flow, Transporter, and Enzyme Interactions on the Processing of Digoxin in Rat Liver

Liu

Mak

Tirona

et al. 2005

J Pharmacol Exp Ther

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The roles of vascular binding, flow, transporters, and enzymes as determinants of the clearance of digoxin were examined in the rat liver. Digoxin is metabolized by Cyp3a and utilizes the organic anion transporting polypeptide 2 (Oatp2) and P-glycoprotein (Pgp) for influx and excretion, respectively. Uptake of digoxin was found to be similar among rat periportal (PP) and perivenous (PV) hepatocytes isolated by the digitonin-collagenase method. The K m values for uptake were 180 Ϯ 112 and 390 Ϯ 406 nM, V max values were 13 Ϯ 8 and 18 Ϯ 4.9 pmol/min/mg protein, and nonsaturable components were 9.2 Ϯ 1.3 and 10.7 Ϯ 2.5 l/min/mg for PP and PV, respectively. The evenness of distribution of Oatp2 and Pgp was confirmed by Western blotting and confocal immunofluorescent microscopy. When digoxin was recirculated to the rat liver preparation in Krebs-Henseleit bicarbonate (KHB) for 3 h in absence or presence of 1% bovine serum albumin (BSA) and 20% red blood cell (rbc) at flow rates of 40 and 10 ml/min, respectively, biexponential decays were observed. Fitted results based on compartmental analyses revealed a higher clearance (0.244 Ϯ 0.082 ml/min/g) for KHB-perfused livers over the rbc-albuminperfused livers (0.114 Ϯ 0.057 ml/min/g) (P Ͻ 0.05). We further found that binding of digoxin to 1% BSA was modest (unbound fraction ϭ 0.64), whereas binding to rbc was associated with slow on (0.468 Ϯ 0.021 min Ϫ1) and off (1.81 Ϯ 0.12 min Ϫ1 ) rate constants. We then used a zonal, physiologically based pharmacokinetic model to show that the difference in digoxin clearance was attributed to binding to BSA and rbc and not to the difference in flow rate and that clearance was unaffected by transporter or enzyme heterogeneity.Digoxin, an important cardiotonic drug of narrow therapeutic index, is cleared by both the kidney and liver, and exhibits a long half-life in vivo due to the large volume of distribution (Kramer et al., 1974;Rodin and Johnson, 1988). In the rat liver, digoxin is primarily metabolized by cytochrome P450 3a to the didigitoxoside and monodigitoxoside as well as digitoxigenin (Harrison and Gibaldi, 1976; Sal- ABBREVIATIONS:Pgp, P-glycoprotein; Oatp, rat organic anion transporting polypeptide; OAT, organic anion transporter; PP, periportal; PV, perivenous; rbc, red blood cell; KHB, Krebs-Henseleit bicarbonate buffer; BSA, bovine serum albumin; PBPK, physiologically based pharmacokinetic; Dg3, unlabeled digoxin; Dg2, digitoxigenin bis-digitoxoside; Dg1, digitoxigenin monodigitoxoside; Dg0, digitoxigenin; HPLC, high-performance liquid chromatography; HRP, horseradish peroxidase; Hct, hematocrit; AUC, area under the curve; A 2 , Dg3 amount in peripheral compartment; A bile and A met , amounts of Dg3 excreted into bile and metabolized, respectively; C 1 , Dg3 concentration in central compartment (compartmental modeling); C R (or Dg3 R ), Dg3 concentration in the reservoir; C rbc,R (or Dg3 rbc,R ), Dg3 concentration in rbc in the reservoir; C p,R (or Dg3 p,R ), Dg3 concentration in plasma, in the reservoir; C rbci...

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“…The involvement of CYP3A in the pharmacokinetic interaction of Dx has been explained by the increased metabolism of Dx in rat following the chronic administration of pregnenolone 16a-carbonitrile or spironolactone, which are inducers of this enzyme (Klaassen, 1974;Wirth and Frolich, 1974). However, the use of rat as a model to predict or explain the drug interaction of Dx in human is not appropriate because of the differences in the handling of this drug between the two species.…”

Section: Discussionmentioning

confidence: 97%

Pharmacokinetic interaction with digoxin and glucocorticoids in rats detected by radio-immunoassay using a novel specific antiserum

et al. 2005

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Effect of spironolactone on excretion of 3H-digoxin and its metabolites in rats

Cited by 23 publications

References 17 publications

P-Glycoprotein and an Unstirred Water Layer Barring Digoxin Absorption in the Vascularly Perfused Rat Small Intestine Preparation: Induction Studies with Pregnenolone-16α-carbonitrile

P-Glycoprotein and an Unstirred Water Layer Barring Digoxin Absorption in the Vascularly Perfused Rat Small Intestine Preparation: Induction Studies with Pregnenolone-16α-carbonitrile

Vascular Binding, Blood Flow, Transporter, and Enzyme Interactions on the Processing of Digoxin in Rat Liver

Pharmacokinetic interaction with digoxin and glucocorticoids in rats detected by radio-immunoassay using a novel specific antiserum

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