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

1 Studies with knockout mice lacking mdrla P-glycoprotein (P-gp) have previ ously shown that blood-brain barrier P-gp is important in preventing the ac cumulation of several drugs in the brain. 2 Asimadoline (EMD 61753) is a peripherally selective kappa-opioid receptor agonist which is under development as a therapeutic analgaesic. From the s tructural characteristics of this drug and its peripheral selectivity, we h ypothesized that it is transported by P-gp. 3 Using a pig-kidney polarized epithelial cell line transfected with mdr cD NAs, we demonstrate that asimadoline is transported by the mouse mdrla P-gp and the human MDRI P-gp. 4 Furthermore, we show that in mdr 1a/1b double knockout mice, the absence of P-gp leads to a 9 fold increased accumulation of asimadoline in the brai n. In line with this accumulation difference, mdr 1a/1b (-/-) mice are at l east 8 fold more sensitive to the sedative effect of asimadoline than wild- type mice. 5 Interestingly, the oral uptake of asimadoline was not substantially alter ed in mdr 1a/1b (-/-) mice. 6 Our results demonstrate that for some drugs, P-gp in the blood-brain barr ier can have a therapeutically beneficial effect by limiting brain penetrat ion, whereas at the same time intestinal P-gp is not a significant impedime nt to oral uptake of the drug.