Looking at PK data #2

Here is a parallel set of data comparing young healthy adults and patients with cirrhosis. Again, this set of data is not meant to prove changes which happen in cirrhosis but more as an exercise to explore and understand PK effects.

As in the previous post, the first thing that strikes you is the massive changes in AUC seen in cirrhotics. The AUC for cirrhotics is 1.85 times that of the young. By the same logic as in the previous post this AUC increase is inversely related to a decrease in clearance and/or bioavailability. Since there is no way to assess bioavailability in this set of data, we shall leave it out of the discussion for the time being. It is not that the cirrhosis did not result in a change of bioavailability, it is just that the experimental design does not allow us to examine bioavailability effects.

Unlike the situation with the elderly, the reduction in clearance in cirrhotics is not accompanied by a fall in the unbound fraction. Instead, the unbound fraction is elevated from 3.5 to 5.3%. Changes in protein binding is not uncommon in liver cirrhosis. Often serum albumin is reduced. Here the protein binding is decreased with a corresponding increase in the free fraction. In fact the increase in free fraction has the effect of actually increasing metabolic clearance.The reduction in clearance is therefore not a result of a decrease free fraction, but primarily due to loss of enzyme activity. One can in addition, expect that the extent of degradation of enzyme activity is even greater than indicated by the extent of decrease of clearance because part of this effect is mitigated by an increased clearance caused by the increase in free fraction.

The increase in elimination halflife and corresponding fall in Kel is related to the reduction in clearance. The magnitude of the change in halflife is however larger than the fall in clearance and suggests that perhaps the Vd may have increased as well. This is expected because of the increase in free fraction.