TPGS (similar other excipients) may transiently inhibit intestinal P-gp and improve oral exposure, but translation to humans is uncertain and does not address BBB efflux. One of the primary mitigation is through chemistry (e.g removing P-gp motifs, improving permeability).
Any other thoughts from anyone with P-gp/BBB experience, what would you do here?
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Pankajini Mallick Ph.D.
Sr. Principal Scientist, DMPK, PK/PD
San Diego CA
Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
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Original Message:
Sent: 09-26-2025 00:59
From: Pankajini Mallick
Subject: P-gp substrate liability
Molecules are advanced based on overall developability and not eliminated solely for being P-gp substrates. P-gp is not a stand-alone kill criterion, instead it's managed contextually, screened in tiers, and weighed alongside potency, ADME, safety margins, and projected human dose.
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Pankajini Mallick Ph.D.
Sr. Principal Scientist, DMPK, PK/PD
San Diego CA
Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
Original Message:
Sent: 09-25-2025 12:35
From: Anonymous Member
Subject: P-gp substrate liability
This message was posted by a user wishing to remain anonymous
Hi all,
How do companies manage chemical that are P-gp substrate during drug discovery and development? Do they use TPGS in the formulation to inhibit P-gp and increase the potency of chemicals (i.e. IC50 or IC90 is 1 pg/mL) for the target while the interaction of the chemical with P-gp could be in ug range? What are the other strategies? Do companies rank order (or eliminate) compounds based on P-gp liability?
Thanks in advance!
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