The development of pharmaceutical drugs is a long process: It takes about 12 years before a substance can be brought onto the market. Before a substance is produced, in silico and in vitro screenings in cells or organoid cultures are performed, as well as preclinical test studies on animals and clinical trials with healthy volunteers.

First a large number of molecules (up to 10,000) is examined using a computer to determine whether there might be a suitable test substance amongst them. There are computer programs that for instance investigate whether a molecule is capable of binding to a cellular receptor or how it theoretically could be metabolized by enzymes, etc. The substance is then tested in cell cultures to see how it behaves on or in the cells. If these results are promising, animal experiments are carried out (regulatory toxicity studies). An important aspect is determining whether the substance is actually bioavailable in different animals.

Bioavailability is the availability of a substance administered extravascularly (i.e. outside the blood or lymph vessels) for its desired effect, or in other words: how much actually that reaches systemic circulation and thus can be transported to its target site. If a substance is ingested, its amount is usually reduced by incomplete absorption via the gastric and intestinal mucosae and the so-called pre-systemic metabolism in the intestinal mucosa and liver. The latter process is called the first-pass effect. Knowledge of the extent of these processes is of immense importance, for instance for determining correct substance dosages and calculating how often/at what intervals a substance must be taken. In some cases the substance is excreted quickly before it can reach the site of action, thus the bioavailability is low and the substance ineffective.

Since testing on humans is preceded by tests on animals, the animal tests must also display sufficient bioavailability. Some manufacturers only start the development of a substance if meets a minimum bioavailability threshold of 20 per cent (*).

In his recent database and literature research, Dr. Wolfgang Boomgaarden has now found that many “blockbuster drugs” - for instance omeprazole, aripiprazole or duloxetine - fell short of this threshold in animal tests, whereas bioavailability in humans is quite high - a classic case of species differences. So why were these drugs developed anyway? And conversely: How many substances are not developed due to low bioavailability in animals, although they could be very effective in humans?

Dr. Wolfgang Boomgaarden, founder and head of PharmInformatic, intends to use his expert system on bioavailability to help answer just such questions before animal tests are conducted, thus reducing the use of animals whenever possible.

Click here to read the article:
http://www.pharmainformatic.com/html/blockbuster_drugs.html

* Literature:
Veber, DF, Johnson, SR, Cheng, H-Y, Smith, BR, Ward, KW & Kopple, KD (2002): Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. J. Med. Chem. 45: 2615-2623.

Omeprazole is a drug from the group of proton pump inhibitors and is used to treat gastric and duodenal ulcers, and reflux oesophagitis. Its bioavailability in human is 35 per cent, increasing to 60 per cent when administered repeatedly.

Duloxetine is a drug used for treating depression and generalized anxiety disorders. The absolute oral bioavailability in humans varies enormously between 32 per cent and 80 per cent, depending on the patient. This is due to a considerable variability in the first-pass effect depending on gender, age, smoking, diet and the activity of the xenobiotic enzyme CYP2D6.

Aripiprazole is a drug used for treating schizophrenia and moderate to severe manic phases of Bipolar I disorder, and for preventing new manic episodes. Oral bioavailability in humans is 87 per cent.