ChEMBL

Off work ill at the moment, snotty child on lap, and the new Marvel Avengers film on DVD. Anyway, the opening scene got me thinking, "I wonder if there are any good reversible 3A4 inhibitors that are great substrates for one of the other liver P450s". That tells you how good the movie is.

Imagine you've got Drug A, which is a great drug iv, but has poor oral bioavailability due to gut 3A4 metabolism when orally dosed. Now imagine, you co-dose with Drug B, which is a gut-specific 3A4 inhibitor, to improve the bioavailability/reduce efficacious dose of Drug A.

So the basic idea is to see if it's possible to improve bioavailability by inhibition of gut wall 3A4 by another drug - of course, the original drug will still probably be good liver 3A4 feedstock as well, but it may be a way of improving of PK for poorly behaved drugs. If that 3A4 inhibitor was also a good substrate for another liver localised P450, like 1A2, 2C9, 2C19, or 2D6, there would be low systemic exposure of this compound, and potential subsequent reduction of DDIs since the 3A4 in the liver would be largely spared, etc. i.e. the gut 3A4 inhibitor had high first pass metabolism, and would in effect be a functional gut-specific 3A4 inhibitor. 

I guess some of these other liver P450s are polymorphic, so, avoiding 2D6 and 2C19 may be worthwhile.

Of course, this is in an area ripe for DDIs, induction of non-linear PK, etc., but if anyone knows of any pre-existing studies, or specific examples of drugs that have something approaching this effect, I'd be really interested. So, if you know any examples, post them in the comments!

P.S. A sort of related 'systems biology' view of modulating drug metabolism would involve the use of bacterial glucoronidase inhibitors to reduce enterohepatic recirculation (these would need to stay in the gut and have no systemic exposure). Regorafenib is an example of a drug with potentially serious liver tox. and undergoes enterohepatic recirculation but I don't know if it is glucoronidated, or indeed the route of excretion - but i may well try to find out.