Drug–Drug Interactions within Protein Cavities Probed by Triplet–Triplet Energy Transfer

A new direct and noninvasive methodology based on transient absorption spectroscopy has been developed to probe the feasibility of drug–drug interactions within a common protein binding site. The simultaneous presence of (<i>R</i>)-cinacalcet (CIN) and (<i>S</i>)-propranolol (PPN) within human or bovine α₁-acid glycoproteins (AAGs) is revealed by detection of ³CIN* as the only transient species after laser flash photolysis of CIN/PPN/AAG mixtures at 308 nm. This is the result of triplet–triplet energy transfer from ³PPN* to CIN, which requires close contact between the two drugs within the same biological compartment. Similar results are obtained with nabumetone and CIN as donor/acceptor partners. This new methodology can, in principle, be extended to a variety of drug/drug/biomolecule combinations