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The following message was posted to: PharmPK
Hello all,
I have searched the literature and have been unable to find any
references leading to the predictability of maximum absorbed dose
(MAD) and/or intact drug bioavailability in the presence of gut
efflux transporters (passive absorption). For the time being, I will
assume complete drug is solubilized throughout the gut. Can anyone
provide insight and/or references. Initially, I suppose one could
also assume one efflux transporter, with the ratio of permeability
values bidirectionally known. Also, if one is using a program such as
GastroPlus or Simcyp, it would be helpful (if not proprietary
information) to provide the equations. Thanks.
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The following message was posted to: PharmPK
Dear Clerk,
Marija Tubic, Peter Langguth, and I have published a paper
recently, describing a GastroPlus model for the non-linear dose
dependence of talinolol absorption due to saturation of Pgp. We
describe pitfalls going from in vitro measurements to in vivo
prediction. We're working on another article that describes the
application of the model to prediction of controlled release.
GastroPlus is pretty much of an open book simulation program. We
don't supply source code but the equations are described in the
following publications.
Tubic M, Wagner D, Spahn-Langguth H, Bolger MB, Langguth P.
In silico modeling of non-linear drug absorption for the P-gp
substrate talinolol and of consequences for the resulting
pharmacodynamic effect.
Pharm Res. 2006 Aug;23(8):1712-20.
PMID: 16832615 [PubMed - indexed for MEDLINE]
http://www.springerlink.com/content/m323560555x8uv25/
Bolger MB, Agoram B. Fraczkiewicz R, and Steer B: (2003) "Simulation
of absorption, metabolism, and bioavailability." In "Drug
Bioavailability. Estimation of Solubility, Permeability and
Bioavailability, for the Series Methods and Principles in Medicinal
Chemistry ", ed. Han van de Waterbeemd , published by Wiley
Publishers 2002.
Bolger MB, Gilman TM, Fraczkiewicz R, Steere B, and Woltosz W: (2002)
"Predicting drug absorption by computational methods." In "Cell
Culture Models of Biological Barriers: In-vitro test systems for Drug
Absorption and Delivery", ed. C.M. Lehr, Saarbruecken, Germany; by
Taylor & Francis, London, UK.
Agoram B, Woltosz WS, and Bolger MB: (2001) Predicting the impact of
physiological and biochemical processes on oral drug bioavailability.
Adv. Drug. Deliv. Rev. 50:S41-S67.
Yu LX, Lipka E, Crison JR, Amidon GL.
Transport approaches to the biopharmaceutical design of oral drug
delivery systems: prediction of intestinal absorption.
Adv Drug Deliv Rev. 1996 Jun 12;19(3):359-76. Review.
Mike
* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *
* Michael B. Bolger, Ph.D.
* Chief Scientist
* Phone: (661) 723-7723 x 301
* FAX: (661) 723-5524
* Simulations Plus, Inc.
* 42505 10th Street West
* Lancaster, CA 93534
* U.S.A.
* http://www.simulations-plus.com (AMEX: SLP)
* bolger.-at-.simulations-plus.com
* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *
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