Subject: Summary of Oral Bioavailability question.

From: "Kirby, Robert" <[email-masked]>
Date: Thu, 23 May 96 10:54:00 PDT

CCL,
 A couple of weeks ago I posted a question to the list asking for any   
available info on oral bioavailability as an issue in drug design. I did   
not receive a lot of answers to my question but the ones I did receive   
were quite helpful. Here is a short list of rules I have extracted from   
my investigations.
1. Consider this early in drug design if this is an issue since leaving   
it to the end will often be a disaster.
2. Keep molecular weights down (500 g/mol is a commonly sited value to   
stay below).
3. Keep the logP value between 0.5 and 4.0 (these values may vary   
depending on the system, molecular weight, number of hydrogen bond donors   
and this can be quite different if you hit an active transport).
4. This is associated with 3 but stay away from charged groups in the   
molecule.
5. There are active transport mechanisms with definable pharmacophores   
one example being for tripeptides and like compounds (ie phealapro) which   
are zwitterionic at physiological pH and these can be used to transport   
drugs into the blood stream.

I am still collecting refs on this and if anyone runs across any then I   
would appreciate them.

Here are a few important refs I have found:

 Pharm Res (UNITED STATES)   Oct 1994,  11 (10) p1405-13,  ISSN 0724-8741
 Int. J. Pharm.  DATE: 1991  VOLUME: 76  NUMBER: 1-2  PAGES, 37-47
 Pharmaceutical Research (New York) 12 (9 SUPPL.). 1995.  S306.
 Journal of Controlled Release, 13(1990) 141-146.
 Pharmaceutical Research, Vol.8, No.12,1991, p.1453.
 Pharmaceutical Research, Vol.13, No.1,1996, p.120.

Here are the responses to my question and many thanks to those who helped   
by responding:

 !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!  
!!!!!!!!!! 
  Robert A. Kirby
  BioChem Therapeutiques Inc.
  275 Armand-Frappier Blvd.
  Laval, Quebec,
  H7V 4A7
  #514-978-7914
  fax 514-978-7777
  [email-masked]
 !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!  
!!!!!!!!!!

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

About one year ago, there was a similar query in CCL. Somehow I kept such   

a concise summary which I forward to you as following. Hope it help.

Best wishes,

Arthur

_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/
_/   Arthur Wang                     Doctoral Candidate     _/
_/   Molecular Design Lab                                   _/
_/   Institute of Physical Chemistry, Peking University     _/
_/   Beijing 100871, P.R.China                              _/
_/                                                          _/
_/   E-mail: [email-masked]                          _/
_/   Tel: 86-10-2751490    Fax: 86-10-2751725               _/
_/   WWW: http://www.ipc.pku.edu.cn/moldes/arthur/home.html _/
_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/

Dear Readers,

I would be grateful for comments, ideas, anecdotes, references etc. on   
the
following topic:

In the area of drug research, a frequent problem which arises is that of
obtaining oral-availability: it is usually more desirable to have an   
orally
active compound than one which is active only when injected.

What I want to know is the following:

1  Is it possible to predict whether a compound will be orally active?

2  On observing a compound has little or no oral activity, are there any
   structural modifications which can be used to increase the oral   
activity
   of the compound?

3  Is it possible to use an adjuvant to increase the absorption of a
   weakly orally active compound?

4  Are there any in vitro test systems which will predict whether a
   compound is orally active? If there are such test systems, are they
   available commercially or have they been devloped in-house?

I will summarise useful information to the net.

Andy Sheppard
Ferring Research Institute
[email-masked]

[crossposted to newsgroups bionet.general, bionet.molbio.methds-reagnts,
 bionet.molec-model and the Computational Chemistry list]

 --------------------------------------------------------------------------  
 -
I suggest you look at the following references:

Taylor, Lynch and Leahy "Models for intestinal permeability to drugs" in   
Drug
Delivery to the Gastrointestinal Tract, pub. Ellis Horwood, 1989, page   
147. -
this is a discussion of model systems for drug absorption using rat   
jejunum
and
ileum as well as model solvent systems. Subsequent to this work, this   
group
(Zeneca) has tried QSAR approaches for prediction of absorption with
considerable success, although I don't think that is published in detail.

Hill et al, Headache (1994) 34: 308 "Oral delivery of 5HT1D receptor
agonists"
 - this is a short account of the Wellcome group's use of physical   
property
measurements (both experimental and calculated) to improve the
bioavailability
of a series of compounds.

Conradi et al, Pharm. Res. (1991) 8: 1453 "Influence of Peptide Structure   
on
Transport Across CACO-2 Cells" - discusses CACO-2 cells as a model for   
drug
absorption. Absorption seems to increase with removal of H-bond donors.   
Other
authors have reported the same.

I consider the 3 refs above to be "highlights". Some other papers of
potential
interest are:

Hirono et al, Biol Pharm Bull (1994) 17:306 - QSAR approach
Amidon and Lee, Annu Rev Pharmacol Toxicol (1994) 34:321 - Review of   
peptide
absorption
Paterson et al, QSAR (1994) 13:4 - Solvent system
Ranadive et al, Pharm Res (1994) 9:1480 - ACE inhibitors
Taylor et al, J Pharm Pharmacol (1985) 37:280 - Beta-blockers
Nook et al. J Pharmaceutics (1988) 43:119 - Relationship between   
partition
coefficients and absorption kinetics
Karls et al, Pharm Res (1991) 8:1477 - The importance of desolvation   
energy

You can get software to predict solubility and lipophilicity, and also
metabolism.  Empirically, most CNS active agents (and most "typical"
drugs) seem to have an octanol/aqueous partition coefficient of logP = 2
(approx).  But this depends upon class, e.g. penicillins are much more
hydrophilic.  A good strategy might be to try to approximate the   
phys-chem
properties of known structurally related orally active compounds
(solubility and log P (oct).
Hope this helps.  Contact me off-line for informaiton on software.

Some basic pharmacophore modeling of the intestinal peptide carrier has
been described in a Dutch doctoral thesis:
P.W. Swaan, Prodrug targetting to the intestinal peptide carrier: an   
approach
for increasing oral bioavailability, University of Utrecht, December 15,   
1993
(ISBN 90-9006574-1). I figure this one will be difficult to find.

An interesting recent review on oral availability is:
Navia, M.A. and P.R. Chaturvedi, Drug Discovery Today, 1, 179-189, 1996