Abstract
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 kappa-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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP Binding Cassette Transporter, Subfamily B / deficiency
-
ATP Binding Cassette Transporter, Subfamily B / genetics
-
ATP Binding Cassette Transporter, Subfamily B / metabolism
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / deficiency
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
-
ATP-Binding Cassette Sub-Family B Member 4
-
ATP-Binding Cassette Transporters / genetics
-
ATP-Binding Cassette Transporters / metabolism
-
Acetamides / metabolism*
-
Acetamides / pharmacokinetics
-
Acetamides / toxicity
-
Analgesics, Opioid / metabolism*
-
Analgesics, Opioid / pharmacokinetics
-
Analgesics, Opioid / toxicity
-
Animals
-
Biological Availability
-
Blood-Brain Barrier / physiology*
-
Brain / drug effects
-
Brain / metabolism*
-
Cell Line
-
Humans
-
Male
-
Mice
-
Mice, Knockout
-
Pyrrolidines / metabolism*
-
Pyrrolidines / pharmacokinetics
-
Pyrrolidines / toxicity
-
Sleep Stages / drug effects*
-
Swine
-
Tissue Distribution
Substances
-
ATP Binding Cassette Transporter, Subfamily B
-
ATP Binding Cassette Transporter, Subfamily B, Member 1
-
ATP-Binding Cassette Transporters
-
Acetamides
-
Analgesics, Opioid
-
Pyrrolidines
-
multidrug resistance protein 3
-
asimadoline