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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............
BITS-Pilani, Hyderabad Campus,
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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.
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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/).
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