P‐glycoprotein‐mediated transcellular transport of MDR‐reversing agents

Saeki, Tohru; Ueda, Kazumitsu; Hori, Ryohei; Komano, Tohru

doi:10.1016/0014-5793(93)81540-g

Cited by 107 publications

(81 citation statements)

References 15 publications

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“…Therefore, ticlopidine might possible increase absorption of carvedilol in the intestine through the inhibition of CYP2C9. In addition to its extensive metabolism by CYP2C9, carvedilol appeared to be the substrate of P-gp, suggesting that P-gp and CYP2C9 should act synergistically to limit the oral bioavailability of carvedilol (Saeki et al, 1993). Therefore, we investigated the cell-based P-gp activity using rhodamne-123 and the result showed that ticlopidine did not affect P-gp activity.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Drug Interaction between Carvedilol and Ticlopidine in Rats

Choi¹

2010

Biomolecules and Therapeutics

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-This study was designed to investigate the effects of ticlopidine on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats. Carvedilol was administered orally (3 mg/kg) or intravenously (1 mg/kg) without or with oral administration of ticlopidine (4, 12 mg/kg) to rats. The effects of ticlopidine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 activity were also evaluated. Ticlopidine inhibited CYP2C9 activity in a concentration-dependent manner with 50% inhibition concentration (IC 50 ) of 25.2 μM. In addition, ticlopidine could not significantly enhance the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group (given carvedilol alone), the area under the plasma concentration-time curve (AUC) was significantly (12 mg/kg, p＜0.05) increased by 14-41%, and the peak concentration (C max ) was significantly (12 mg/kg, p＜0.05) increased by 10.7-73.3% in the presence of ticlopidine after oral administration of carvedilol. Consequently, the relative bioavailability (R.B.) of carvedilol was increased by 1.14-to 1.41-fold and the absolute bioavailability (A.B.) of carvedilol in the presence of ticlopidine was increased by 36.2-38.5%. Compared to the i.v. control, ticlopidine could not significantly change the pharmacokinetic parameters of i.v. administered carvedilol. The enhanced oral bioavailability of carvedilol may result from inhibition of CYP2C9-mediated metabolism rather than P-gpmediated efflux of carvedilol in the intestinal and/or in liver and renal eliminatin of carvedilol by ticlopidine.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Drug Interaction between Carvedilol and Ticlopidine in Rats

Choi¹

2010

Biomolecules and Therapeutics

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“…These latter modulators compete for outward transport of the MDR-related drugs (e.g. cyclosporin A, FK-506, azidopine I-NAPS, and ivermectin) [94,116,170,171].…”

Section: Specific Inhibitorsmentioning

confidence: 99%

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

Safa

2004

CMCACA

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A major problem in cancer treatment is the development of resistance to multiple chemotherapeutic agents in tumor cells. A major mechanism of this multidrug resistance (MDR) is overexpression of the MDR1 product P-glycoprotein, known to bind to and transport a wide variety of agents. This review concentrates on the progress made toward understanding the role of this protein in MDR, identifying and characterizing the drug binding sites of P-glycoprotein, and modulating MDR by P-glycoprotein-specific inhibitors. Since our initial discovery that Pglycoprotein binds to vinblastine photoaffinity analogs, many P-glycoprotein-specific photoaffinity analogs have been developed and used to identify the particular domains of Pglycoprotein capable of interacting with these analogs and other P-glycoprotein substrates. Furthermore, significant advances have been made in delineating the drug binding sites of this protein by studying mutant P-glycoprotein. Photoaffinity labeling experiments and the use of sitedirected antibodies to several domains of this protein have allowed the localization of the general binding domains of some of the cytotoxic agents and MDR modulators on P-glycoprotein. Moreover, site-directed mutagenesis studies have identified the amino acids critical for the binding of some of these agents to P-glycoprotein. Furthermore, equilibrium binding assays using plasma membranes from MDR cells and radioactive drugs have aided our understanding of the modes of drug interactions with P-glycoprotein. Based on the available data, a topological model of Pglycoprotein and the approximate locations of its drug binding sites, as well as a proposed classification of multiple drug binding sites of this protein, is presented in this review.

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“…Substrates for the human MDRllPgp include peptides such as valinomycin [lo], gramicidin D [l 11, cyclosporin A [12], a tripeptide N-acetyl-leucyl-leucyl-norleucinal [13], and yeast afactor mating peptide [14]. During our search for peptide antibiotics which interact with human Pgp, we found that Saccharomyces cerevisiae expressing human MDRllPgp showed resistance to aureobasidin A, a new antifungal cyclic depsipeptide antibiotic produced by Aureobasidium pullulans R106 [15,16].…”

Section: Introductionmentioning

confidence: 99%