Cleavage of digoxigenin digitoxosides by rat liver microsomes

Schmoldt, A.; Ahsendorf, B

doi:10.1007/bf03189468

Cited by 4 publications

(2 citation statements)

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“…However, digoxin is extensively metabolized by cytochrome P4503A in rats (>70% of an i.p. dose) (Harrison and Gibaldi 1976;Schmoldt and Ahsendorf 1980;Shitara et al 2002). Contrary to the situation in rats, there is no convincing information from clinical studies in man, whether inhibitors of intestinal P-glycoprotein may influence hepatic uptake of digoxin.…”

Section: Limitations Of Digoxinmentioning

confidence: 96%

In Vivo Probes of Drug Transport: Commonly Used Probe Drugs to Assess Function of Intestinal P-glycoprotein (ABCB1) in Humans

Oswald

Terhaag

Siegmund

2010

Handbook of Experimental Pharmacology

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Intestinal P-glycoprotein (P-gp, ABCB1) may significantly influence drug absorption and elimination. Its expression and function is highly variable, regio-selective and influenced by genetic polymorphisms, drug interactions and intestinal diseases. An in vivo probe drug for intestinal P-gp should a registered, safe and well tolerated nonmetabolized selective substrate with low protein binding for which P-gp is rate-limiting during absorption. Other P-gp dependent processes should be of minor influence. The mechanism(s) and kinetics of intestinal uptake must be identified and quantified. Moreover, the release properties of the dosage form should be known. So far, the cardiac glycoside digoxin and the ß₁-selective blocker talinolol have been used in mechanistic clinical studies, because they meet most of these criteria. Digoxin and talinolol are suitable in vivo probe drugs for intestinal P-gp under the precondition, that they are used as tools in carefully designed pharmacokinetic studies with adequate biometrically planning of the sample size and that several limitations are considered in interpreting and discussion of the study results.

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Section: Limitations Of Digoxinmentioning

confidence: 96%

In Vivo Probes of Drug Transport: Commonly Used Probe Drugs to Assess Function of Intestinal P-glycoprotein (ABCB1) in Humans

Oswald

Terhaag

Siegmund

2010

Handbook of Experimental Pharmacology

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“…dose) by cytochrome P450 3A (CYP3A) in rat (Harrison and Gibaldi, 1976;Schmoldt and Ahsendorf, 1980;Rodin and Johnson, 1988). Thus, we hypothesized that the regulation of the uptake/metabolism/efflux pathway for digoxin by Oatp2, CYP3A, and P-gp might be affected in the presence of uptake (Oatp2) and efflux transporter (P-gp) inhibitors.…”

mentioning

confidence: 99%

Ex Situ Inhibition of Hepatic Uptake and Efflux Significantly Changes Metabolism: Hepatic Enzyme-Transporter Interplay

Lau¹,

Wu²,

Okochi³

et al. 2003

J Pharmacol Exp Ther

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The disposition of digoxin and the influence of the organic anion transporting polypeptide (Oatp)2 inhibitor rifampicin and the P-glycoprotein (P-gp) inhibitor quinidine on its hepatic disposition were examined in the isolated perfused rat liver. Livers from groups of rats were perfused in a recirculatory manner after a bolus dose of digoxin (10 g), a dual substrate for Oatp2 and P-gp as well as CYP3A. Perfusions of digoxin were also examined in groups of rats in the presence of the inhibitors: rifampicin (100 M) or quinidine (10 M). In all experiments, perfusate samples were collected for 60 min. Digoxin and its primary metabolite were determined in perfusate and liver by liquid chromatography/mass spectrometry. The area under the curve (AUC) from 0 to 60 min was determined. The AUC Ϯ S.D. of digoxin was increased from control (3880 Ϯ 210 nM⅐min) by rifampicin (5200 Ϯ 240 nM⅐min; p Ͻ 0.01) and decreased by quinidine (3220 Ϯ 340 nM⅐min; P Ͻ 0.05). It is concluded that rifampicin limits the hepatic entrance of digoxin and reduced the hepatic exposure of digoxin to CYP3A by inhibiting the basolateral Oatp2 uptake transport, whereas quinidine increased the hepatic exposure of digoxin to CYP3A by inhibiting the canalicular P-gp transport. These data emphasize the importance of uptake and efflux transporters on hepatic drug metabolism.

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