Method of improving bioavailability of orally administered drugs, a method of screening for enhancers of such bioavailability and novel pharmaceutical compositions for oral delivery of drugs

Abstract

A method for increasing the systemic exposure of cells selected from tumor cells and normal cells to an orally administered pharmaceutically active compound, wherein a bioenhancer comprising an inhibitor of BCRP is orally administered concomitantly with said orally administered pharmaceutically active compound, and in which method the inhibitor is administered simultaneously with the pharmaceutical compound.

1 . A method for increasing the systemic exposure of cells selected from tumor cells and normal cells to an orally administered pharmaceutically active compound, comprising: 
 orally administering a bioenhancer comprising an inhibitor of BCRP and said pharmaceutically active compound, wherein said inhibitor and said pharmaceutically active compound are concomitantly exposed to said cells.    
   
   
       2 . Method according to  claim 1 , wherein the inhibitor is administered simultaneously with the pharmaceutical compound.  
   
   
       3 . Method according to  claim 1 , wherein the cells are normal cells.  
   
   
       4 . Method according to  claim 1 , wherein the inhibitor is a selective inhibitor of BCRP.  
   
   
       5 . Method according to  claim 1 , wherein the inhibitor is selected from acridine derivatives, quinoline derivatives, isoquinoline derivatives and combinations thereof.  
   
   
       6 . Method according to  claim 1 , wherein the inhibitor is XR 9051 or XR 9576.  
   
   
       7 . Method according to  claim 1 , wherein the bioenhancer is a mycotoxin.  
   
   
       8 . Method according to  claim 7 , wherein the mycotoxin is fumitremorgin C.  
   
   
       9 . Method according to  claim 1 , wherein the bioenhancer has a higher affinity for BCRP than for P-gp.  
   
   
       10 . Method according to  claim 1 , wherein the bioenhancer has a higher affinity for BCRP than for MRP.  
   
   
       11 . Method according to  claim 1 , wherein the bioenhancer inhibits binding of ATP to a BCRP mediated and/or related drug transport protein.  
   
   
       12 . Method according to  claim 11 , wherein the protein is BCRP.  
   
   
       13 . Method according to  claim 1 , wherein the pharmaceutically active compound is selected from the group consisting of indolizino-quinoline derivatives, camptothecin derivatives, anthraquinone derivatives and quinazoline derivatives.  
   
   
       14 . Method according to  claim 13 , wherein the pharmaceutically active compound is an indolizino-quinoline derivative.  
   
   
       15 . Method according to  claim 13 , wherein the pharmaceutically active compound is a camptothecin derivative.  
   
   
       16 . Method according to  claim 15 , wherein the pharmaceutically active compound is selected from the group consisting of topotecan, GG211, DX8951f, BNP1350, 9-aminocamptothecin, 9-nitrocamptothecin, CPT11 and any metabolites thereof.  
   
   
       17 . Method according to  claim 16 , wherein the metabolite is SN38.  
   
   
       18 . Method according to  claim 13 , wherein the pharmaceutically active compound is an anthraquinone derivative.  
   
   
       19 . Method according to  claim 18 , wherein the pharmaceutically active compound is mitoxantrone.  
   
   
       20 . Method according to  claim 13 , wherein the pharmaceutically active compound is a quinazoline derivative.  
   
   
       21 . Method according to  claim 20 , wherein the pharmaceutically active compound is prazosin.  
   
   
       22 . Pharmaceutical composition comprising a bioenhancer and a pharmaceutically active compound, said bioenhancer comprising an inhibitor of BCRP and said pharmaceutically active compound being selected from the group consisting of indolizino-quinoline derivatives, camptothecin derivatives, anthraquinone derivatives and quinazoline derivatives.  
   
   
       23 . Animal having inactive BCRP and/or being free of BCRP.  
   
   
       24 . A method of screening for a compound useful for increasing bioavailability of an orally administered drug in a mammal, said drug being transported via the BCRP related or mediated drug transport system by assaying a candidate compound for inhibition of transport by BCRP and selecting a compound exhibiting such inhibition, in particular exhibiting such inhibition in the gut or gastrointestinal tract.