Drugs racemised in-vivo
The following table shows some of the most common (not an exhaustive list) of drugs racemised in-vivo.
Since the biological targets are necessarily chiral, the molecules formed upon epimerisation (inversion at the centre being racemised) are usually inactive against the desired target (annoying, but ultimately fine), issues only arise when the epimerised molecule has its own biological activity, which is often undesirable (for instance in the case of toxicity of thalidomide).
[![Commonly racemised drugs][1]][1]
Pathways of racemisation
The mechanisms by which drugs are racemised is not always well known/studied (i.e. it isn't always possible to pin down the exact thing responsible, however two generalised 'mechanistic pathways' have been proposed: 1
formation of a covalent intermediate followed by a stepwise enzyme-catalyzed transformation
interaction of two opposing metabolic processes, such as oxidation and reduction
One thing that is generally agreed upon, is that the racemisation is the result of more than simple deprotonation/protonation (such as the way chiral centres adjacent to aldehydes tend to epimerise), since the pH in the body is, in most places, not basic enough to do so.
The interconversion of (R) and (S) ibuprofen is one example where a mechanism has been proposed, and involves multiple intermediates:
[![enter image description here][2]][2]
1: Curr. Drug Metab. 2004, 5, 517–533.
Apologies for the lack of reference to the table, it was taken from a set of lecture notes, though I suspect the lecturer had previously copied it from the primary literature somewhere [1]: https://i.sstatic.net/TU4iW.png [2]: https://i.sstatic.net/mF9XN.png