In addition to its effects on potency and selectivity, there is also evidence that macrocyclization can affect important pharmaceutical properties related to the absorption, distribution, metabolism, and excretion (ADME) of the compound when administered in vivo. For example, by constraining the conformations available to the compound, cyclization might make it more difficult for the compound to fit into the active site of metabolic enzymes such as cytochrome P450s (CYPs), reducing its susceptibility to degradation. This effect can reduce the compound's metabolic clearance rate, and thereby increase its pharmacokinetic half-life. There are few documented examples of such effects among the macrocyclic kinase inhibitors that are the focus of this article, however. An exception is the PI3Kd inhibitor from Spencer et al., 37 (Figure ) which, while showing little discernible increase in human, pig, or rat liver microsome or hepatocyte stability in vitro, displayed 20-fold lower clearance in vivo in comparison to its acyclic precursor 36, as well as a surprising 5-fold decrease in volume of distribution despite having a 2.7 unit higher value for logDpH7.4. Examples of effects on metabolic stability of macrocycles addressing other target classes include the antiviral clinical candidate TMC 647055, which targets the hepatitis C virus NS5B polymerase, for which Cummings et al. report that macrocyclization resulted in substantial improvement in bioavailability and pharmacokinetic properties compared to the acyclic precursor. Similar macrocyclization-related ADME effects have been reported for macrocycles directed at melanocortin receptor-4 (MC4R), the dengue virus NS3 protease, and the nicotinic acetyl choline receptor, nAChR. It is likely that similar effects will apply to kinasedirected macrocycles.