Abstract
Purpose. The purpose of this study was to investigate whether midazolam exhibits characteristics of a highly permeable P-glycoprotein (P-gp) substrate and to evaluate the potential influence of P-gp inhibition on 1-OH midazolam formation during midazolam transport.
Methods. P-gp interaction was investigated by P-gp ATPase assay, efflux inhibition studies, and transport studies of midazolam across MDR1-MDCK and 1-α,25-dihydroxy vitamin D3-induced Caco-2 monolayers with and without the P-gp inhibitor GF120918.
Results. Midazolam was highly permeable and transport appeared essentially unpolarized. In MDR1-MDCK, the basolateral-to-apical (B-to-A) permeability was slightly higher (16%) than apical-to-basolateral (A-to-B) permeability (p = 0.04); GF120918 increased A-to-B permeability by 27% (p = 0.01), and increased cellular midazolam accumulation during A-to-B transport by 45% (p = 0.01). Midazolam (200 μM) decreased rhodamine123 and vinblastine B/A ratios 3-fold (p < 0.006), while increasing their cellular accumulation (p < 0.003). P-gp ATPase activation by midazolam was dose-dependent and saturable [K m=11.5(±4.0) μM; V max = 41.1(±7.4) nmol/mg/min]. P-gp inhibition increased 1-OH midazolam formation in A-to-B studies 1.3-fold when midazolam donor ≥ μM (p < 0.03). In B-to-A studies, P-gp inhibition did not significantly increase metabolite formation (p = 0.06). Midazolam's extraction ratio was not influenced by P-gp (p = 0.2).
Conclusions. The results indicate that midazolam exhibited characteristics of a highly permeable P-gp substrate. 1-OH midazolam formation during A-to-B midazolam transport increased slightly when P-gp was inhibited.
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Tolle-Sander, S., Rautio, J., Wring, S. et al. Midazolam Exhibits Characteristics of a Highly Permeable P-Glycoprotein Substrate. Pharm Res 20, 757–764 (2003). https://doi.org/10.1023/A:1023433502647
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DOI: https://doi.org/10.1023/A:1023433502647