Evaluation of Drug Interactions with P-Glycoprotein in Drug Discovery: In Vitro Assessment of the Potential for Drug-Drug Interactions with P-Glycoprotein

Hochman, Jerome H.; Yamazaki, Masayo; Ohe, Tomoyuki; Lin, Jiunn H.

doi:10.2174/1389200023337559

Cited by 108 publications

(60 citation statements)

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“…There are at least two possible explanations for the difference in results between these two studies. First, even though murine-human differences in P-gp substrate recognition and transport seem modest for most substrates (Yamazaki et al, 2001;Hochman et al, 2002;Takeuchi et al, 2006), there might be species differences in the P-gp-mediated transport of alfentanil. This study evaluated the in vivo effects of murine P-gp (mdr1a), whereas the previous work studied the human form of P-gp (MDR1) in vitro.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Alfentanil in P-Glycoprotein-Competent and P-Glycoprotein-Deficient Mice: P-Glycoprotein Efflux Alters Alfentanil Brain Disposition and Antinociception

Kalvass

Olson²,

Pollack³

2006

Drug Metab Dispos

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ABSTRACT:Previous studies have indicated that P-glycoprotein (P-gp) attenuates the central nervous system penetration and central activity of some opioids. The impact of P-gp-mediated efflux on the disposition and efficacy of the synthetic opioid alfentanil currently is unknown. In this study, P-gp-competent [mdr1a(؉/؉)] and P-gpdeficient [mdr1a(؊/؊)] mice were used to investigate the impact of P-gp-mediated efflux on the systemic pharmacokinetics, brain disposition, and central activity of alfentanil. Equipotent doses of alfentanil were administered to mdr1a(؉/؉) and mdr1a(؊/؊) mice (0.2 and 0.067 mg/kg, respectively), and the time course of brain and serum concentrations as well as antinociception were determined. A pharmacokinetic-pharmacodynamic (PK-PD) model was fit to the data and used to assess the impact of P-gp on parameters associated with alfentanil disposition and action. The mdr1a(؉/؉) mice were less sensitive to alfentanil than mdr1a(؊/؊) mice, requiring a 3-fold higher dose to produce similar antinociception. PK-PD modeling revealed no differences in alfentanil systemic pharmacokinetics between P-gp expressers and nonexpressers. However, the steady-state brain-to-serum concentration ratio (K p,brain,ss ) was ϳ3-fold lower in mdr1a(؉/؉) mice compared with mdr1a(؊/؊) mice (0.19 ؎ 0.01 versus 0.54 ؎ 0.04, respectively). Consistent with the ϳ3-fold lower K p,brain,ss , the antinociception versus serum concentration relationship in mdr1a(؉/؉) mice was shifted ϳ3-fold rightward compared with mdr1a(؊/؊) mice. However, there was no difference in the antinociception versus brain concentration relationship, or in the brain tissue EC 50 (11 ؎ 1.8 versus 9.2 ؎ 1.7 ng/g), between mdr1a(؉/؉) and mdr1a(؊/؊) mice. These results indicate that alfentanil is an in vivo P-gp substrate and are consistent with the hypothesis that P-gp-mediated efflux attenuates antinociception by reducing alfentanil K p,brain,ss .

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Alfentanil in P-Glycoprotein-Competent and P-Glycoprotein-Deficient Mice: P-Glycoprotein Efflux Alters Alfentanil Brain Disposition and Antinociception

Kalvass

Olson²,

Pollack³

2006

Drug Metab Dispos

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“…Physicochemical properties are critical to the absorption, distribution, metabolism, and excretion of different xenobiotic compounds. However, it has now become apparent that different transport proteins play an important role in regulating the kinetic disposition of several drugs (Hochman et al, 2002). In addition, clinically relevant drug interactions may occur after the concomitant administration of different compounds.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the P-Glycoprotein-Mediated Intestinal Secretion of Ivermectin: In Vitro and in Vivo Assessments

Ballent¹,

Lifschitz²,

Virkel³

et al. 2005

Drug Metab Dispos

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ABSTRACT:The everted gut sac method was used to assess the role of the P-glycoprotein (P-gp) on the intestinal secretion of ivermectin (IVM), an antiparasitic widely used in human and veterinary medicine. The work included the evaluation of two different P-gp modulators [itraconazole (ITZ) and valspodar (PSC833)] used at equimolar doses in the rat. Furthermore, the influence of both P-gp modulator agents on the disposition kinetics of IVM in plasma, liver, and gastrointestinal tissues was characterized.

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“…All of the compounds that interacted with P-gp had 2 or more hydrogen bond acceptors (electron donors) separated by 4.6 Å or 3 acceptors positioned 2.5 Å from each other. While this model needs further validation, some recent studies within homologous structural series suggest a correlation between hydrogen bond acceptor potential and the ability of compounds to interact with P-gp (193). Pharmacophore models for in silico prediction of P-gp substrate and modulators have been generated.…”

Section: In-silico Predictionmentioning

confidence: 99%

Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

Bansal¹,

Jaggi²,

Khar³

et al. 2009

J Pharm Pharm Sci

208

161

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Chemotherapy forms the mainstay of cancer treatment particularly for patients who do not respond to local excision or radiation treatment. However, cancer treatment by drugs is seriously limited by P-glycoprotein (P-gp) associated multi-drug resistance (MDR) in various tumor cells. On the other hand, it is now widely recognized that P-gp also influences drug transport across various biological membranes. P-gp transporter is widely present in the luminal surface of enterocytes, biliary canalicular surface of hepatocytes, apical surface of proximal tubular cells of kidney, endothelial cells of blood brain barrier, etc. thus affecting absorption, distribution, metabolism and excretion of xenobiotics. Clinical significance of above mentioned carrier is appreciated from the fact that more than fifty percent of existing anti-cancer drugs undergo inhibitable and saturable P-gp mediated efflux. Consequently, there is an increasing trend to optimize pharmacokinetics, enhance antitumour activity and reduce systemic toxicity of existing anti-cancer drugs by inhibiting P-gp mediated transport. Although a wide variety of P-gp inhibitors have been discovered, research efforts are underway to identify the most appropriate one. Flavonoids (polyphenolic herbal constituents) form the third generation, non-pharmaceutical category of P-gp inhibitors. The effects produced by some of these components are found to be comparable to those of well-known P-gp inhibitors verapamil and cyclosporine. Identification of effective P-gp modulator among herbal compounds have an added advantage of being safe, thereby making them ideal candidates for bioavailability enhancement, tissue-penetration (e.g. blood brain barrier (BBB)), decreasing biliary excretion and multi-drug resistance modulating agents. The dual effects, i.e. P-gp modulation and antitumor activity, of these herbal derivatives may synergistically act in cancer chemotherapy. This paper presents an overview of the investigations on the feasibility and application of flavonoids as P-gp modulators for improved efficacy of anti-cancer drugs like taxanes, anthracyclines, epipodophyllotoxins, camptothecins and vinca alkaloids. The review also focuses on flavonoid-drug interactions as well as the reversal activity of flavonoids useful against MDR. In addition, the experimental models which could be used for investigation on P-gp mediated efflux are also discussed.

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Evaluation of Drug Interactions with P-Glycoprotein in Drug Discovery: In Vitro Assessment of the Potential for Drug-Drug Interactions with P-Glycoprotein

Cited by 108 publications

References 0 publications

Pharmacokinetics and Pharmacodynamics of Alfentanil in P-Glycoprotein-Competent and P-Glycoprotein-Deficient Mice: P-Glycoprotein Efflux Alters Alfentanil Brain Disposition and Antinociception

Pharmacokinetics and Pharmacodynamics of Alfentanil in P-Glycoprotein-Competent and P-Glycoprotein-Deficient Mice: P-Glycoprotein Efflux Alters Alfentanil Brain Disposition and Antinociception

Modulation of the P-Glycoprotein-Mediated Intestinal Secretion of Ivermectin: In Vitro and in Vivo Assessments

Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

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