Phase I metabolism may either detoxify or toxify. Phase I reactions produce a more polar molecule that is easier to eliminate. Phase I reactions can sometimes result in a substance more toxic than the originally ingested substance. An example is the Phase I metabolism of acetonitrile

The Liver Oral administration frequently brings the drugs (via the portal system) to the liver

Metabolism of Drugs (cont.) Phase II metabolism links the drug to still more polar molecules to render them even more easy to excrete

Metabolism of Drugs (cont.) Another Phase II reaction is sulfation (shown below)

Phase II Metabolism Phase II reactions most commonly detoxify Phase II reactions usually occur at polar sites, like COOH, OH, etc.

Manufacture of Drugs Pharmaceutical companies must make a profit to continue to exist Therefore, drugs must be sold at a profit One must have readily available, inexpensive starting materials One must have an efficient synthetic route to the compound –As few steps as possible –Inexpensive reagents

The route must be suitable to the “scale up” needed for the production of at least tens of kilograms of final product This may limit the structural complexity and/or ultimate size (i.e. mw) of the final product In some cases, it may be useful to design microbial processes which produce highly functional, advanced intermediates. This type of process usually is more efficient than trying to prepare the same intermediate using synthetic methodology.

Toxicity Toxicity standards are continually becoming tougher Must use in vivo (i.e. animal) testing to screen for toxicity –Each animal is slightly different, with different metabolic systems, etc. –Thus a drug may be toxic to one species and not to another

Example: Thalidomide Thalidomide was developed by German pharmaceutical company Grünenthal. It was sold from 1957 to 1961 in almost 50 countries under at least 40 names. Thalidomide was chiefly sold and prescribed during the late 1950s and early 1960s to pregnant women, as an antiemetic to combat morning sickness and as an aid to help them sleep. Before its release, inadequate tests were performed to assess the drug's safety, with catastrophic results for the children of women who had taken thalidomide during their pregnancies. Antiemetic = a medication that helps prevent and control nausea and vomiting