Influence of passive permeability on apparent P-glycoprotein kinetics.

Article Details

Citation

Lentz KA, Polli JW, Wring SA, Humphreys JE, Polli JE

Influence of passive permeability on apparent P-glycoprotein kinetics.

Pharm Res. 2000 Dec;17(12):1456-60.

PubMed ID
11303953 [ View in PubMed
]
Abstract

PURPOSE: The objectives of this work were to evaluate the importance of moderate passive permeability on apparent P-glycoprotein (P-gp) kinetics, and demonstrate that inspection of basolateral to apical and apical to basolateral (BL-AP/AP-BL) permeability ratios may result in a compound being overlooked as a P-gp substrate and inhibitor of another drug's transport via P-gp inhibition. METHODS: The permeability ratios of nicardipine, vinblastine, cimetidine, and ranitidine were determined across Caco-2 monolayers that express P-gp, in the presence and absence of the specific P-gp inhibitor, GF120918. In addition, the permeability ratio of vinblastine was studied after pretreatment of Caco-2 monolayers with nicardipine, ranitidine, or cimetidine. Similar studies were repeated with hMDRI-MDCK monolayers. RESULTS: The permeability ratios for cimetidine and vinblastine were >2. The permeability ratios for nicardipine and ranitidine were close to unity, and were not affected by the addition of GF120918. Based solely on ratios, only compounds with moderate transcellular permeability (vinblastine and cimetidine) would be identified as P-gp substrates. Although the permeability ratios appeared to be unity for nicardipine and ranitidine, both compounds affected the permeability of vinblastine, and were identified as substrates and inhibitors of P-gp. Studies performed in hMDR1-MDCK cells confirmed these experimental results. Data were explained in the context of a kinetic model, where passive permeability and P-gp efflux contribute to overall drug transport. CONCLUSIONS: Moderate passive permeability was necessary for P-gp to reduce the AP-BL drug permeability. Inspection of the permeability ratio after directional transport studies did not effectively identify P-gp substrates that affected the P-gp kinetics of vinblastine. Because of the role of passive permeability, drug interaction studies with known P-gp substrates, rather than directional permeability studies, are needed to elucidate a more complete understanding of P-gp kinetics.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
CimetidineP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inducer
Details
NicardipineP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Details
RanitidineP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Details