PharmPK Discussion - P-gp modulation on permeability of P-gp substrate

• On 10 Mar 2011 at 15:05:33, rahul vats (rahulvats1983.at.gmail.com) sent the message
  

  
  Dear all,
  
  I would like to know the possible effect of P-gp modulation on  permeability of P-gp substrate
  
  1) Whether permeability will remain constant in SPIP model or  irrespective of any model
  2) Whether modulator (P-gp inhibitor) can change the permeability in  SPIP model (analysing drug disappearance from the loop)
  
  i am working on drug-drug interaction: where one drug is substrate of  both P-gp and gut CYP-3A4 and another drug is inhibitor of both.Now i  would like to know the drug interaction at absorption level and the  reason of drug interaction individually (P-gp modulation or CYP 3A4  modulation).To gather this kind of information which model(s) will be  appropriate.
  
  Looking forward for your expert comments............
  -- Regards,
  
  Rahul Vats
  BITS-Pilani, Hyderabad Campus,
  
  

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• On 11 Mar 2011 at 20:12:16, Mitul Patel (mitulgpatel.at.ymail.com) sent the message
  

  
  Dear Rahul,
  If your molecule is Pgp inhibitor then in closed loop, you may get lower  concentraions as it will also block intestinal pgp so most probably drug  absorption will be higher.
  
  For 2 drugs for which 1 is substrate and another is inhibitor of both,  you'll have to go for determination of IC50 for PgP Inhibition and IC50  for CYP3A4 inhibition as well (InVitro).
  From these IC50 data u'll come to know whether the drug is either PgP  or CYP3A4 dominant Inhibitor.
   For PgP Inhibition you can opt CaCo2 cell line (Based on Efflux Ratio  Index) and for CYP3A4 you may go for Human Liver Microsomes for IC50  determination.   Hope this will help you out somewhat.
   Regards,
   Mitul Patel
  
  

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• On 13 Mar 2011 at 10:54:23, Masoud Jamei (masoud.jamei.-at-.gmail.com) sent the message
  

  
  Hi Rahul
  
  Interplay of enzymes and transporters in the gut even without any  interaction is a hot topic and different views are expressed in  literature, for example see:
  
  Benet LZ (2009) The Drug Transporter-Metabolism Alliance: Uncovering and  Defining the Interplay. Molecular Pharmaceutics 6:1631-1643.
  
  Custodio JM, Wu CY and Benet LZ (2008) Predicting drug disposition,  absorption/elimination/transporter interplay and the role of food on  drug absorption. Adv Drug Deliv Rev 60:717-733.
  
  Sun H and Pang K (2010) Physiological Modeling to Understand the Impact  of Enzymes and Transporters on Drug and Metabolite Data and  Bioavailability Estimates. Pharmaceutical Research 27:1237-1254.
  
  Fan J, Maeng H-J and Pang S (2010) Interplay of Transporters and Enzymes  in the Caco-2 Cell Monolayer: I. Effect of altered apical secretion.  Biopharmaceutics & Drug Disposition.
  
  Due to the complex nature of this interplay and different drug-dependent  and physiological factors involved it isn't trivial to predict the final  outcome, please see the following report where more than 8500  simulations were carried out to investigate the effects of only 5  parameters.
  
  Darwich AS, Neuhoff S, Jamei M and Rostami-Hodjegan A (2010) Interplay  of Metabolism and Transport in Determining Oral Drug Absorption and Gut  Wall Metabolism: A Simulation Assessment Using the "Advanced  Dissolution, Absorption, Metabolism (ADAM)" Model. Curr Drug Metab  11:716-729.
  
  Prediction of transporters-mediated interaction and determining P-gp  IC50 are even more challenging and these are going to be debated at:  "AAPS Workshop on Drug Transporters in ADME: From the Bench to the  Bedside"  (http://www.aapspharmaceutica.com/meetings/workshops/DrugTrans/).
  Regards
  Masoud
  
  

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