Role of P-glycoprotein in pharmacokinetics and drug interactions of digoxin and β-methyldigoxin in rats

Funakoshi, Sachiyo; Murakami, Teruo; Yumoto, Ryoko; Kiribayashi, Yoshie; Takano, Mikihisa

doi:10.1002/jps.10416

Cited by 23 publications

(16 citation statements)

References 33 publications

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“…The relationship between biliary excretion and metabolism seems to be inversely correlated. Compounds with high biliary excretion are often poorly metabolized [such as digoxin (Caldwell and Cline 1976;Funakoshi et al, 2003), methotrexate (Henderson et al, 1965a;Fahrig et al, 1989), and pravastatin (Hatanaka 2000)], whereas those that are highly metabolized generally show poor biliary excretion [such as dasatinib and BMS-182874) (Chong et al, 2003;Kamath et al, 2008)]. Furthermore, many carboxylic acid-containing compounds in the present study were poorly metabolized by rat liver microsomes (data not shown) and showed a high biliary excretion.…”

Section: Luo Et Almentioning

confidence: 49%

“…When the same computational model was applied to 25 structurally diverse compounds whose rat biliary excretion data were published by different laboratories (Hirom et al, 1972b;Russell and Klaassen 1973;Fahrig et al, 1989;Monsarrat et al, 1990;Masuda et al, 1997;Hinchman et al, 1998;Payan et al, 1999;Song et al, 1999;Arimori et al, 2003;Chong et al, 2003;Funakoshi et al, 2003;Moriwaki et al, 2003;Kamath et al, 2005aKamath et al, ,b, 2008Kurihara et al, 2005;Takayanagi et al, 2005;Akashi et al, 2006;Beconi et al, 2007), the predicted and observed biliary excretion values were again very close for most compounds. The clear exceptions were cephradine and paclitaxel (Monsarrat et al, 1990;Moriwaki et al, 2003).…”

Section: Luo Et Almentioning

confidence: 78%

See 1 more Smart Citation

In Silico Prediction of Biliary Excretion of Drugs in Rats Based on Physicochemical Properties

Luo¹,

Johnson²,

Hsueh³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Evaluating biliary excretion, a major elimination pathway for many compounds, is important in drug discovery. The bile ductcannulated (BDC) rat model is commonly used to determine the percentage of dose excreted as intact parent into bile. However, a study using BDC rats is time-consuming and cost-ineffective. The present report describes a computational model that has been established to predict biliary excretion of intact parent in rats as a percentage of dose. The model was based on biliary excretion data of 50 Bristol-Myers Squibb Co. compounds with diverse chemical structures. The compounds were given intravenously at <10 mg/kg to BDC rats, and bile was collected for at least 8 h after dosing. Recoveries of intact parents in bile were determined by liquid chromatography with tandem mass spectrometry. Biliary excretion was found to have a fairly good correlation with polar surface area (r ‫؍‬ 0.76) and with free energy of aqueous solvation (⌬G solv aq ) (r ‫؍‬ ؊0.67). In addition, biliary excretion was also highly corrected with the presence of a carboxylic acid moiety in the test compounds (r ‫؍‬ 0.87). An equation to calculate biliary excretion in rats was then established based on physiochemical properties via a multiple linear regression. This model successfully predicted rat biliary excretion for 50 BMS compounds (r ‫؍‬ 0.94) and for 25 previously reported compounds (r ‫؍‬ 0.86) whose structures are markedly different from those of the 50 BMS compounds. Additional calculations were conducted to verify the reliability of this computation model.Biliary excretion is a major elimination pathway for many drugs and discovery compounds both in humans and in preclinical animals. For example, pravastatin and losoxantrone were found to be mainly eliminated as intact parent through biliary excretion in humans (Hatanaka 2000;Joshi et al., 2001). In rats, pravastatin and methotrexate were minimally metabolized and were primarily excreted intact into bile (Masuda et al., 1997;Kurihara et al., 2005). Extensive biliary excretion can be linked to a high clearance (Arimori et al., 2003), enterohepatic recirculation (Caldwell and Cline 1976;Rollins and Klaassen 1979), toxic gastrointestinal side effects (Kato et al., 2002), and potential drug-drug interactions (Luo et al., 2007). As a result, most lead discovery compounds are assessed for biliary excretion in selected preclinical animals early in the drug discovery and development process.Among the preclinical animal models, rats are the most commonly used model species for pharmacology, pharmacokinetics, and toxicology. The existing experimental models for determining rat biliary excretion include bile duct-cannulated rats and isolated perfused rat liver. However, these models are very time-consuming and costineffective because of complicated preparation of test models and difficulty in bile sample analyses.Undoubtedly, a computational model for predicting rat biliary excretion could significantly reduce laboratory efforts and, consequently, cost. Furthermore, a...

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Section: Luo Et Almentioning

confidence: 49%

Section: Luo Et Almentioning

confidence: 78%

In Silico Prediction of Biliary Excretion of Drugs in Rats Based on Physicochemical Properties

Luo¹,

Johnson²,

Hsueh³

et al. 2009

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…PE-50 tubing was inserted ∼1 cm into the duodenum and fixed with surgical sutures (Dogsan Surgical Sutures, Trabzon, Turkey) for ID digoxin administration. After the cannulation procedure was completed, rats received either digoxin ID (200 µg/kg [Salphati and Benet 1998], 150 µL) or IV (10 µg/kg [Funakoshi et al 2003], 200 µL). The study groups were digoxin ID , n = 8; digoxin ID OPT, n = 8; digoxin IV , n = 8; and digoxin IV OPT, n = 8.…”

Section: Methodsmentioning

confidence: 99%

Effect of Repeated Low-Dose Organophosphorothionate Pesticide Exposure on Digoxin Pharmacokinetics in Rats; a Possible Interaction Involving P-Glycoprotein

Yusuf

Oransay

Eminoglu³

et al. 2007

Toxicology Mechanisms and Methods

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Aside from acute occupational exposure, an important part of the population may be chronically exposed to the trace amounts of organophosphorothionate pesticides (OPTs) via residues in nutrients and drinking water. P-glycoprotein (P-gp) is a transmembrane protein responsible for the efflux of numerous drugs. OPTs were shown to inhibit P-gp function in vitro and increase its expression in vivo. Digoxin is a probe drug for the investigation of P-gp. To evaluate the effect of repeated low-dose OPT exposure on P-gp, commercial formulations of diluted OPT or tap water were administered to female Wistar rats for 8 consecutive days. On the ninth day each group was further divided into two groups and digoxin was administered either intraduodenally (ID) or intravenously (IV). Blood sampling and bile and urine collection were taken during 6 h at various intervals. The peak concentration in serum (C(max)) of digoxin was found to be decreased and the mean absorption time (MAT) was significantly increased in the digoxin OPT group. The mean residence time was significantly elevated in the digoxin(ID) OPT group. The biliary excretion% digoxin was significantly increased in the digoxin OPT group, while the renal excretion% digoxin rose only in the digoxin(ID) OPT group. No significant differences in time to reach C(max) (t(max)), area under the plasma concentration-time curve (AUC)(0-360), area under the moment curve (AUMC)(0-360), and bioavailability (F) were detected. In our study, repeated low-dose OPT exposure reduced the absorption and increased the excretion% digoxin, which may be related to enhanced P-gp expression. However, alterations of digoxin pharmacokinetic parameters did not change the systemic availability of digoxin.

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“…CYP3A4 and Pgp are believed to play competing roles in drug absorption, metabolism, and elimination (Pang, 2003). Because many prototypic inhibitors and inducers affect both the enzyme and Pgp, significant drug-drug interactions for digoxin that involve one or both of these systems have been reported (Su and Huang, 1996;Greiner et al, 1999;Drescher et al, 2003;Funakoshi et al, 2003).…”

mentioning

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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Role of P-glycoprotein in pharmacokinetics and drug interactions of digoxin and β-methyldigoxin in rats

Cited by 23 publications

References 33 publications

In Silico Prediction of Biliary Excretion of Drugs in Rats Based on Physicochemical Properties

In Silico Prediction of Biliary Excretion of Drugs in Rats Based on Physicochemical Properties

Effect of Repeated Low-Dose Organophosphorothionate Pesticide Exposure on Digoxin Pharmacokinetics in Rats; a Possible Interaction Involving P-Glycoprotein

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

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