P‐glycoprotein‐mediated intestinal and biliary digoxin transport in humans

Drescher, Siegfried; Glaeser, Hartmut; Mürdter, Thomas E.; Hitzl, Monika; Eichelbaum, Michel; Fromm, Martin F.

doi:10.1067/mcp.2003.27

Cited by 144 publications

(139 citation statements)

References 20 publications

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“…The impact of Pgp on oral bioavail-ability, intestinal excretion, and tissue distribution has been shown in mdr1a knockout mice (Schinkel et al, 1997a;Sparreboom et al, 1997). In humans, Pgp inhibition caused a significant decrease in digoxin intestinal excretion (Drescher et al, 2003), whereas rifampinup-regulated intestinal Pgp expression appeared to be responsible for a decrease in digoxin oral bioavailability (Greiner et al, 1999).…”

Section: Saquinavir [Sqv (N-tert-butyl-decahydro-2-[2(r)-hydroxy-4-pmentioning

confidence: 99%

Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and CYP3A on Saquinavir Oral Absorption in Sprague-Dawley Rats

Usansky¹,

Hu²,

Sinko³

2008

Drug Metab Dispos

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ABSTRACT:The objective of this investigation was to differentiate the roles of P-glycoprotein (Pgp), multidrug resistance-associated protein 2 (Mrp2), and CYP3A on saquinavir ( -(((3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl) ((3-(dimethylamino-3-oxopropyl)thio)methyl)-thio) propanoic acid (MK571)], and/or CYP3A (midazolam). Plasma concentrations of SQV and related metabolites were analyzed by liquid chromatography-tandem mass spectrometry. When given alone, SQV absorption was extremely low both in situ (F a ‫؍‬ 0.07%) and in vivo [C max ‫؍‬ 0.068 g/ml; area under the curve (AUC) ‫؍‬ 6.8 g ⅐ min/ml]. Coadministration of GF120918 boosted SQV absorption by more than 20-fold with decreased variation in AUCs (percent coefficient of variation ‫؍‬ 30% versus 100%). In contrast, coadministration of MK571 or midazolam increased SQV absorption only 2-to 3-fold without improving the variation in AUCs. SQV oral absorption was not further improved when it was given with GF120918 and midazolam or with GF120918 and MK571. The current results provide, for the first time, direct and explicit evidence that the low oral absorption of SQV is controlled by a secretory transporter, Pgp, and not by limited passive diffusion owing to its poor physicochemical properties. Pgp-mediated transport is also responsible for the highly variable oral bioavailability of SQV. In contrast, intestinal Mrp2 and intestinal CYP3A appear to play minor roles in SQV oral bioavailability. Given the differential and complex roles of Pgp and CYP3A in SQV oral absorption, the optimization of AIDS boosting regimens requires careful consideration to avoid therapylimiting drug-drug transporter and enzyme interactions.

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Section: Saquinavir [Sqv (N-tert-butyl-decahydro-2-[2(r)-hydroxy-4-pmentioning

confidence: 99%

Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and CYP3A on Saquinavir Oral Absorption in Sprague-Dawley Rats

Usansky¹,

Hu²,

Sinko³

2008

Drug Metab Dispos

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“…Inhibition of the P-gp transporter may also be the basis for drug-drug interactions. The classic example is the increase in oral bioavailability of digoxin when coadministered with the P-gp inhibitor quinidine (Drescher et al, 2003;Igel et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Development of a Highly Sensitive Method Using Liquid Chromatography-Multiple Reaction Monitoring to Quantify Membrane P-Glycoprotein in Biological Matrices and Relationship to Transport Function

Miliotis¹,

Ali²,

Palm³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The quantification of P-glycoprotein [P-gp, ABCB1, multidrug resistance 1 (MDR1)] protein in biological matrices is considered a key factor missing for useful translation of in vitro functional data to the in vivo situation and for comparison of transporter data among different in vitro models. In the present study a liquid chromatography (LC)-mass spectrometry method was developed to quantify P-gp membrane protein levels in different biological matrices. The amount of P-gp transporter protein was measured in Caco-2 cell monolayers and in inside-out human embryonic kidney (HEK)-MDR1 vesicles. From both in vitro systems, two preparations with different functionality were used. Transporter function was determined as digoxin efflux in Caco-2 cell monolayers and N-methylquinidine (NMQ) uptake in membrane vesicles, and, in addition, mRNA expression in the Caco-2 monolayers was measured. The results showed an excellent relationship between NMQ uptake functionality in inside-out HEK-MDR1 vesicles and protein contents. Similar concordance between the digoxin efflux and P-gp content in different Caco-2 cell cultures was observed, whereas mRNA levels are indicative of increased P-gp content and activity in older Caco-2 cultures, however, not yielding the same quantitative relationship. The results from both Caco-2 and HEK-MDR1 membrane vesicles confirm that the protein content is directly related to the level of activity in the respective system. The method presented here to quantify P-gp protein by LC-multiple reaction monitoring will facilitate the development of future methodologies to bridge between expression systems and cell/tissue models and to scale from in vitro models to whole organs.

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“…Demeule et al [38] found that dexamethasone, which is a P-gp inducer, increased P-gp expression in the liver and the lung but reduced the expression of this molecule in the kidney. Transmembrane proteins in each tissue respond differently to inducers, as stated by Drescher et al [39] . AFB 1 is activated via the conversion into AFB 1 8-9 epoxide by cytochrome 450 enzymes, especially CYP1A2 and CYP3A4, and glutathione S-transferases are the most important enzymes for detoxifying AFB 1 in all species, including mice [40][41][42] .…”

Section: Discussionmentioning

confidence: 99%

Aflatoksin B1’in Fare Beynine Geçişi Üzerine BCRP ve P-gp Modülatörlerinin Etkisi

Traş¹,

Gül²,

Üney³

et al. 2016

Kafkas Univ Vet Fak Derg

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This study was conducted to determine whether the plasma and brain concentrations of AFB1 are affected by the modulation of P-gp and BCRP using zosuquidar (ZQR) and prazosin (PRZ), respectively. In this study, a total of 40 healthy adult male BALB/c mice (32±3.7 g) were used. The animals were randomly divided into 5 groups, with 8 animals per group. Group 1 was used for method validation. Group 2 (AF) received intraperitoneal AFB1 at a dose of 20 mg/kg of body weight. Groups 3 (AF+PRZ), 4 (AF+ZQR), and 5 (AF+PRZ+ZQR) received 20 mg/kg of AFB1 intraperitoneally 30 min after the intraperitoneal administration of prazosin (0.3 mg/kg), zosuquidar (25 mg/kg), and prazosin+zosuquidar (0.3 mg/kg prazosin + 25 mg/kg zosuquidar), respectively. Six hours after the administration of AFB1, blood and brain samples were collected from the animals in Groups 2 to 5. AFB1 concentrations were determined using an HPLC system with fluorescence detection. Individual and simultaneous administration of prazosin and zosuquidar significantly reduced the brain concentrations of AFB1 in comparison to a single administration of AFB1 (P<0.05). The brain/plasma ratio of the AF group was higher than that of the other groups (AF+PRZ, AF+ZQR, and AF+PRZ+ZQR) (P<0.05). Inducers of transmembrane proteins, especially BCRP, can be life saving during acute AFB1 poisoning. Keywords: Aflatoxin B1, Brain, Drug transporter proteins, Modulation, Mice Aflatoksin B 1 'in Fare Beynine Geçişi Üzerine BCRP ve P-gp Modülatörlerinin EtkisiÖzet Çalışma, zosuquidar ve prazosin tarafından sırasıyla P-gp ve BCRP modülasyonunun AFB1'in plazma ve beyin konsantrasyonlarının etkileyip etkilemediğini belirlemek için gerçekleştirildi. Bu çalışmada, 40 adet sağlıklı, erkek BALB/c ırkı fare (32±3.7 g) kullanıldı. Hayvanlar her grupta 8 fare olacak şekilde rastgele 5 gruba ayrıldı. Grup 1, metod validasyon çalışmalarında kullanıldı. Grup 2 (AF)'ye AFB1 20 mg/kg dozda intraperitoneal yolla verildi. Grup 3 (AF+PRZ), 4 (AF+ZQR) ve 5 (AF+PRZ+ZQR)'e ise sırasıyla intraperitoneal yolla prazosin (0.3 mg/kg), zosuquidar (25 mg/kg) ve prazosin+zosuquidar (0.3 mg/kg prazosin + 25 mg/kg zosuquidar) uygulamalarından 30 dk. sonra AFB1 20 mg/kg dozda intraperitoneal yolla uygulandı. Grup 2-5'de bulunan hayvanlardan AFB1 uygulamasından sonraki 6. saatte kan ve beyin örnekleri alındı. AFB1 düzeyleri fluoresans dedektör içeren HPLC sisteminde tayin edildi. Prazosin ve zosuquidarın tek ve eşzamanlı uygulanması AFB1'in beyin konsantrasyonlarında sadece AFB1 uygulamasına göre önemli oranda azalmaya neden oldu (P<0.05). AFB1 grubunda AFB1'in beyin/plazma oranı diğer gruplardan (AF+PRZ, AF+ZQR, and AF+PRZ+ZQR) önemli oranda daha yüksekti (P<0.05). Akut AFB1 zehirlenmelerinde özellikle BCRP gibi transmembran proteinlerin indüklenmesi hayatta kalma oranını artırabilir.

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P‐glycoprotein‐mediated intestinal and biliary digoxin transport in humans

Cited by 144 publications

References 20 publications

Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and CYP3A on Saquinavir Oral Absorption in Sprague-Dawley Rats

Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and CYP3A on Saquinavir Oral Absorption in Sprague-Dawley Rats

Development of a Highly Sensitive Method Using Liquid Chromatography-Multiple Reaction Monitoring to Quantify Membrane P-Glycoprotein in Biological Matrices and Relationship to Transport Function

Aflatoksin B1’in Fare Beynine Geçişi Üzerine BCRP ve P-gp Modülatörlerinin Etkisi

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