Oral availability of drugs...

Lynn Bry aj088 at FreeNet.Carleton.CA
Wed Jan 11 01:36:20 EST 1995

>From: mbasd at s-crim1.dl.ac.uk (A. Sheppard)

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

Yes and no..
To cross a membrane (by diffusion at least) the drug has to
be somewhat lipophilic. However, if it is too lipophilic it will
be too insoluble in water to gain access to the membrane.
As far as I know, most drugs absorbed through the GI tract cross
the epithelial membranes via diffusion.

If your drug is exceedingly hydrophilic it is unlikely to be
absorbed orally on its own. A good example of such 
hydrophilic drugs are the aminoglycoside antibiotics. An
orally administered dose is excreted almost entirely in the feces.
If you want to treat GI infections, that's fine. For infections
at other sites, the drug is administered parenterally.

The drug has to withstand stomach pH or be placed with some
carrier that can get it through the stomach to the duodenum.
Many penicillins are inactivated by stomach pH.

You also have to take into account the variety of degredative
enzymes present in the digestive system as well as the 
biochemical capacity of the host microflora to alter or
degrade many compounds. For this reason peptide drugs
(insulin, e.g.) are not given orally.

>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? 

Alter the hydro/lipophilicity... 
Weak acids sometimes have the advantage that they are water
soluble at neutral pH but far more lipophilic at low pH
(in the stomach) when protonated.

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

Possibly, but I don't know of any off-hand.

>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? 

There are certainly in vitro systems for studying permeability
across phospholipid membranes. Permeability in itself won't tell
you if the compound is active orally, but it is an indication that
it can enter the body by diffusing across epithelial membranes.

You could look in most any textbook on Pharmacology to get some
idea of what is needed for a drug to act orally. The book by
Goodman & Gilman should certainly have some information on
the subject.


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