Abstract
Purpose. To study the intrinsic parameters of P-glycoprotein (P-gp) transport and drug-drug interactions at the blood-brain barrier (BBB), as few quantitative in vivo data are available. These parameters could be invaluable for comparing models and predicting the in vivo implications of in vitro studies.
Methods. The brains of P-gp-deficient mice mdr1a(-/-) and wild-type mice were perfused in situ using a wide range of colchicine, morphine, and vinblastine concentrations. The difference between the uptake by the wild-type and P-gp-deficient mice gave the P-gp-linked apparent transport at the BBB. Drug-drug interactions were examined using vinblastine and compounds that bind to P-gp sites (verapamil, progesterone, PSC833) other than the vinblastine site to take into account the multispecific drug P-gp recognition.
Results. P-gp limited the brain uptake of morphine and colchicine in a concentration-independent way up to 2 mM. In contrast, vinblastine inhibited its own P-gp transport with an IC50 of ∼56 μM and a Hill coefficient of ∼4. The vinblastine efflux by P-gp was described by a Km at 16 μM and a maximal efflux velocity, Jmax, of ∼8 pmol s−1 g−1 of brain. Similarly, vinblastine brain transport was increased by inhibiting P-gp as shown by the IC50 ranking, which was PSC833 < verapamil < vinblastine < progesterone.
Conclusions. P-gp is responsible for both capacity-limited and -unlimited transport of P-gp substrates at the mouse BBB. In situ perfusion of mdr1a(\-/\-) and wild-type mouse brains could be used to predict drug-drug interactions for P-gp at the mouse BBB.
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Cisternino, S., Rousselle, C., Debray, M. et al. In Situ Transport of Vinblastine and Selected P-glycoprotein Substrates: Implications for Drug-Drug Interactions at the Mouse Blood-Brain Barrier. Pharm Res 21, 1382–1389 (2004). https://doi.org/10.1023/B:PHAM.0000036911.49191.da
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DOI: https://doi.org/10.1023/B:PHAM.0000036911.49191.da