Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Article Details
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Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J
Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
J Med Chem. 2003 Apr 24;46(9):1716-25.
- PubMed ID
- 12699389 [ View in PubMed]
- Abstract
The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Astemizole P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Cimetidine P-glycoprotein 1 Protein Humans UnknownSubstrateInducerDetails Clotrimazole P-glycoprotein 1 Protein Humans UnknownInhibitorInducerDetails Dexamethasone P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Dexamethasone acetate P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Digoxin P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Etoposide P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Hydrocortisone P-glycoprotein 1 Protein Humans UnknownSubstrateInducerDetails Hydrocortisone aceponate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone acetate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone butyrate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone cypionate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone phosphate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone probutate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone valerate P-glycoprotein 1 Protein Humans UnknownNot Available Details Itraconazole P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Ivermectin P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Ketoconazole P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Mibefradil P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Miconazole P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Morphine P-glycoprotein 1 Protein Humans NoSubstrateDetails Nelfinavir P-glycoprotein 1 Protein Humans NoSubstrateInhibitorInducerDetails Nicardipine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Pimozide P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Quinidine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Ritonavir P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Saquinavir P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Terfenadine P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Vinblastine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails - Binding Properties