Don't Optimize Your Plasma Protein Binding

Here's a very good review article in J. Med. Chem. on the topic of protein binding. For those outside the field, that's the phenomenon of drug compounds getting into the bloodstream and then sticking to one or more blood proteins. Human serum albumin (HSA) is a big player here - it's a very abundant blood protein that's practically honeycombed with binding sites - but there are several others. The authors (from Genentech) take on the disagreements about whether low plasma protein binding is a good property for drug development (and conversely, whether high protein binding is a warning flag). The short answer, according to the paper: neither one.

To further examine the trend of PPB for recently approved drugs, we compiled the available PPB data for drugs approved by the U.S. FDA from 2003 to 2013. Although the distribution pattern of PPB is similar to those of the previously marketed drugs, the recently approved drugs generally show even higher PPB than the previously marketed drugs (Figure 1). The PPB of 45% newly approved drugs is >95%, and the PPB of 24% is >99%. These data demonstrate that compounds with PPB > 99% can still be valuable drugs. Retrospectively, if we had posed an arbitrary cutoff value for the PPB in the drug discovery stage, we could have missed many valuable medicines in the past decade. We suggest that PPB is neither a good nor a bad property for a drug and should not be optimized in drug design.

That topic has come up around here a few times, as could ...

Source: In the Pipeline - August 19, 2014 Category: Chemists Tags: Pharmacokinetics Source Type: blogs