Validation of quinidine as a probe substrate for the in vitro P-gp inhibition assay in Caco-2 cell monolayer

Patil, Anand; D'Souza, Russell; Dixit, Neeta; Damre, Anagha

doi:10.1007/s13318-011-0046-9

Cited by 19 publications

(16 citation statements)

References 13 publications

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“…To confirm this hypothesis, bidirectional transport studies with radiolabeled substances Quinidine, Vinblastine, and Digoxin as well-known substrates of Pgp were performed. [22][23][24][25] For these compounds, a strong improvement of the calculated NERs was achieved. For example, Quinidine displayed a fivefold increase in the NER (Fig.…”

Section: Discussionmentioning

confidence: 91%

“…These first functional results demonstrated a successful establishment of optimized subpopulations of cells for more sensitive transport studies. To confirm this hypothesis, bidirectional transport studies with radiolabeled substances Quinidine, Vinblastine, and Digoxin as well‐known substrates of Pgp were performed . For these compounds, a strong improvement of the calculated NERs was achieved.…”

Section: Discussionmentioning

confidence: 92%

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Establishment of Optimized MDCK Cell Lines for Reliable Efflux Transport Studies

Gartzke

Fricker

2014

Journal of Pharmaceutical Sciences

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 92%

Establishment of Optimized MDCK Cell Lines for Reliable Efflux Transport Studies

Gartzke

Fricker

2014

Journal of Pharmaceutical Sciences

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“…has not yet been established [57] CYP3A4 (I/S) P-gp (I/S) Inducer [29,[54][55][56][57] Tacrolimus 5 mg PO (3 Days) 2 24.9 0.01 0.033 [58], i 0.62 [59] 0.66 [60] , 0.84 [61] 10 [53] , 3.6 [62] CYP3A4…”

Section: Discussionmentioning

confidence: 99%

Intestinal Efflux Transporters P-gp and BCRP Are Not Clinically Relevant in Apixaban Disposition

2020

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Purpose-The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in apixaban disposition based on in vitro studies. Recommendations against co-administration of apixaban with inhibitors of these efflux transporters can be found throughout the literature as well as in the apixaban FDA label. However, the clinical relevance of such findings is questionable due to the high permeability and high solubility characteristics of apixaban.Methods-Using recently published methodologies to discern metabolic-from transportermediated drug-drug interactions, a critical evaluation of all published apixaban drug-drug interaction studies was conducted to investigate the purported clinical significance of efflux transporters in apixaban disposition.Results-Rational examination of these clinical studies using basic pharmacokinetic theory does not support the clinical significance of intestinal efflux transporters in apixaban disposition. Further, there is little evidence that efflux transporters are clinically significant determinants of systemic clearance.Conclusions-Inhibition or induction of intestinal CYP3A4 can account for exposure changes of apixaban in all clinically significant drug-drug interactions, and lack of intestinal CYP3A4 inhibition can explain all studies with no exposure changes, regardless of the potential for these perpetrators to inhibit intestinal or systemic efflux transporters.

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“…In developing and utilizing efflux transporter models, there are a number of variabilities in the assays that can affect the experimental outcomes. Sources of variabilities include the choice of cell line (11,38,39), culture conditions (e.g., cell passage number and monolayer age) (40,41), control substrate or inhibitor specificity (17,42,43), level of transporter expression (44,45), and data analysis (13,19). The objective of this study is to focus on the variability in in vitro inhibition potency determination that may be caused by different calculation methods (e.g., efflux parameters and software programs) from a bidirectional Caco-2 cell assay.…”

Section: Introductionmentioning

confidence: 99%

Use of Different Parameters and Equations for Calculation of IC50 Values in Efflux Assays: Potential Sources of Variability in IC50 Determination

Volpe

Hamed

Zhang

2013

AAPS J

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Drug interactions due to efflux transporters may result in one drug increasing or decreasing the systemic exposure of a second drug. The potential for in vivo drug interactions is estimated through in vitro cell assays. Variability in in vitro parameter determination (e.g., IC₅₀ values) among laboratories may lead to different conclusions in in vivo interaction predictions. The objective of this study was to investigate variability in in vitro inhibition potency determination that may be due to calculation methods. In a Caco-2 cell assay, the absorptive and secretive permeability of digoxin was measured in the presence of spironolactone, itraconazole and vardenafil. From the permeability data, the efflux ratio and net secretory flux where calculated for each inhibitor. IC₅₀ values were then calculated using a variety of equations and software programs. All three drugs decreased the secretory transport of digoxin in a concentration-dependent manner while increasing digoxin's absorption to a lesser extent. The resulting IC₅₀ values varied according to the parameter evaluated, whether percent inhibition or percent control was applied, and the computational IC₅₀ equation. This study has shown that multiple methods used to quantitate the inhibition of drug efflux in a cell assay can result in different IC₅₀ values. The variability in the results in this study points to a need to standardize any transporter assay and calculation methods within a laboratory and to validate the assay with a set of known inhibitors and non-inhibitors against a clinically relevant substrate.

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Validation of quinidine as a probe substrate for the in vitro P-gp inhibition assay in Caco-2 cell monolayer

Cited by 19 publications

References 13 publications

Establishment of Optimized MDCK Cell Lines for Reliable Efflux Transport Studies

Establishment of Optimized MDCK Cell Lines for Reliable Efflux Transport Studies

Intestinal Efflux Transporters P-gp and BCRP Are Not Clinically Relevant in Apixaban Disposition

Use of Different Parameters and Equations for Calculation of IC50 Values in Efflux Assays: Potential Sources of Variability in IC50 Determination

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