Dear Group,Back to the Top
Its given in one paper that "Drugs that are completely absorbed in
humans had Papp values of approximately >1 x 10-6." Basing on
this statement can I make the following statement
Drugs having a Papp value > 1 x 10-6 are completely absorbed in humans,
assuming that metabolism is not playing any role in limiting the
availability.
Regards,
Ravi Kanth
Ravi Kanth Bhamidipati
Research Associate
Dept.of Drug Metabolism and Pharmacokinetics
Discovery Research Division
Dr.Reddy's Laboratories Ltd.
Bollaram Road , Miyapur
Hyderabad - 500 050
Andhra Pradesh
India
At 02:27 AM 4/30/2004, Bhamidipati Ravikanth wrote:Back to the Top
"Its given in one paper that "Drugs that are completely absorbed in
humans had Papp values of approximately >1 x 10-6." Basing on
this statement can I make the following statement
Drugs having a Papp value > 1 x 10-6 are completely absorbed in
humans, assuming that metabolism is not playing any role in limiting
the availability."
No - the amount absorbed (i.e., the amount that crosses the apical
membrane into the enterocytes) can be less than 100% even when Caco-2
Papp is high. There are at least three things to consider:
(1) A Papp value from one lab could be two orders of magnitude
different from the Papp measured in another lab. The value of 1 x 10-6
is for a specific lab.
(2) The drug must first be in solution, and low solubility or slow
dissolution can be rate-limiting. If the in vitro experiment used
solvents (e.g., DMSO) to achieve higher solubility, or if the pH
conditions were such that solubility was significantly higher in vitro
than in vivo, then high Papp might not translate into high absorption.
(3) The conditions of the Caco-2 experiment could be misleading with
respect to human in vivo absorption. Changes in concentrations, apical
and basolateral pH, solvents, transporter expressions, etc. can all
affect the Papp, and correlating Papp with human Peff can sometimes be
difficult.
Of course, absorption (FDA definition = crossing the apical membrane of
the enterocytes) can be high but bioavailability can be low because of
gut wall metabolism and first pass hepatic metabolism. Saquinavir and
midazolam are good examples, both with >80% absorption, but high 3A4
metabolism in the gut wall and liver reduces bioavailability to about
25-30% for midazolam and less than 1% for saquinavir.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-at-.simulations-plus.com
First of all there are some problems with Papp Caco-2 coeficientBack to the Top
1. Inter lab corellation is not very good and you shoul check very
carefully
the assay.
2. In my opinion caco-2 system is not the best descriptor for the
absorption
process (Pgp protein over expressed, other active absorption processes
down
regulated)
And now about your compound absorption:
The main problem here is solubility, if compounds solubility is very
low,
when you will have dose dependent, formulation dependent absorption. the
Caco - 2 system do not account for the solubility (they use cosolvents
or
other solvent systems to solubilise the compound)
Donatas Zmuidinavicius
Pharma Algorithms
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)