Role of blood‐brain barrier P‐glycoprotein in limiting brain accumulation and sedative side‐effects of asimadoline, a peripherally acting analgaesic drug

Studies with knockout mice lacking mdr1a P‐glycoprotein (P‐gp) have previously shown that blood‐brain barrier P‐gp is important in preventing the accumulation of several drugs in the brain. Asimadoline (EMD 61753) is a peripherally selective κ‐opioid receptor agonist which is under development as a therapeutic analgaesic. From the structural characteristics of this drug and its peripheral selectivity, we hypothesized that it is transported by P‐gp. Using a pig‐kidney polarized epithelial cell line transfected with mdr cDNAs, we demonstrate that asimadoline is transported by the mouse mdr1a P‐gp and the human MDR1 P‐gp. Furthermore, we show that in mdr1a/1b double knockout mice, the absence of P‐gp leads to a 9 fold increased accumulation of asimadoline in the brain. In line with this accumulation difference, mdr1a/1b (−/−) mice are at least 8 fold more sensitive to the sedative effect of asimadoline than wild‐type mice. Interestingly, the oral uptake of asimadoline was not substantially altered in mdr1a/1b (−/−) mice. Our results demonstrate that for some drugs, P‐gp in the blood‐brain barrier can have a therapeutically beneficial effect by limiting brain penetration, whereas at the same time intestinal P‐gp is not a significant impediment to oral uptake of the drug.British Journal of Pharmacology (1999) 127 , 43–50; doi: 10.1038/sj.bjp.0702497