title: Exposure of LS-180 cells to drugs of diverse physicochemical and therapeutic properties up-regulates P-glycoprotein expression and activity.
abstract: OBJECTIVE
  Drug transporters are increasingly recognized as important determinants of variability in drug disposition and therapeutic response, both in pre-clinical and clinical stages of drug development process. The role P-glycoprotein (P-gp) plays in drug interactions via its inhibition is well established. However, much less knowledge is available about drugs effect on P-gp up-regulation. The objective of this work was to in vitro investigate and rank commonly used drugs according to their potencies to up-regulate P-gp activity utilizing the same experimental conditions.
  
  
  METHODS
  The in vitro potencies of several drugs of diverse physicochemical and therapeutic properties including rifampicin, dexamethasone, caffeine, verapamil, pentylenetetrazole, hyperforin, and β-estradiol over broad concentration range to up-regulate P-gp expression and activity were examined. For dose-response studies, LS-180 cells were treated with different concentrations of the selected drugs followed by P-gp protein and gene expressions analyses. P-gp functionality was determined by uptake studies with rhodamine 123 as a P-gp substrate, followed by Emax/EC50 evaluation.
  
  
  RESULTS
  The results demonstrated a dose-dependent increase in P-gp expression and activity following treatments. At 50 uM concentration (hyperforin, 0.1 uM), examined drugs increased P-gp protein and gene expressions by up to 5.5 and 6.2-fold, respectively, while enhanced P-gp activity by 1.8-4-fold. The rank order of these drugs potencies to up-regulate P-gp activity was as following: hyperforin >>> dexamethasone ~ beta-estradiol > caffeine > rifampicin ~ pentylenetetrazole > verapamil.
  
  
  CONCLUSIONS
  These drugs have the potential to be involved in drug interactions when administered with other drugs that are P-gp substrates. Further studies are needed to in vivo evaluate these drugs and verify the consequences of such induction on P-gp activity for in vitro-in vivo correlation purposes.
authors: Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, USA.
authors: Alaa H
authors: AH
authors: Abuznait
authors: Shawn G
authors: SG
authors: Patrick
authors: Amal
authors: A
authors: Kaddoumi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D010433:Pentylenetetrazole / Q000494:pharmacology; D004364:Pharmaceutical Preparations; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000494:pharmacology; D020112:Rhodamine 123 / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology; D013268:Stimulation, Chemical; D013729:Terpenes / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations; D013729:Terpenes; D020112:Rhodamine 123; D002110:Caffeine; D004958:Estradiol; D003907:Dexamethasone; D014700:Verapamil; D010696:Phloroglucinol; C001654:hyperforin; D012293:Rifampin; D010433:Pentylenetetrazole