Abstract
The study objectives were to (1) test the hypothesis that the lack of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) inhibition at the blood-brain barrier following cassette dosing of potent P-gp and Bcrp inhibitors was due to low plasma concentrations of those inhibitors and (2) examine the effects of P-gp on the unbound brain (Cu,brain) and cerebral spinal fluid (Cu,CSF) concentrations of P-gp and Bcrp substrates in rats. In vitro inhibition of 11 compounds (amprenavir, citalopram, digoxin, elacridar, imatinib, Ko143, loperamide, prazosin, quinidine, sulfasalazine and verapamil) on P-gp and Bcrp was examined in P-gp-expressing and Bcrp-expressing MDCK cells, respectively. An in vivo study was conducted in wild-type and Mdr1a(-/-) rats following subcutaneous cassette dosing of the 11 compounds at 1-3 mg/kg and the brain, CSF and plasma concentrations of these compounds were determined. At the maximal unbound concentrations observed in rats at 1-3 mg/kg, P-gp and Bcrp were not inhibited by a cassette of the 11 compounds. For non-P-gp/Bcrp substrates, similar Cu,brain, Cu,CSF, and unbound plasma concentrations (Cu,plasma) were observed in wild-type and P-gp knockout rats. For P-gp/Bcrp substrates, Cu,brain ≤ Cu,CSF ≤ Cu,plasma in wild-type rats but Cu,brain and Cu,CSF increased in the P-gp knockout rats and were within 3-fold of Cu,plasma for 6 of the 7 P-gp substrates. These results indicate that P-gp and Bcrp inhibition at the blood-brain barrier is unlikely in cassette dosing and also suggest that P-gp and Bcrp activity at the blood-CSF barrier is functionally not important in determination of the CSF concentration for their substrates.
- The American Society for Pharmacology and Experimental Therapeutics