The net result of chronic hepatic disease that leads to cirrhosis is that pathophysiologic alterations may result in both decreased hepatocyte function, with as much as a 50% decrease in cytochrome P450 content, and/or shunting of blood away from optimally functioning hepatocytes. Accordingly, cirrhosis affects drug metabolism more than does any other form of liver disease. In fact, cirrhosis may decrease the clearance of drugs that are nonrestrictively eliminated in subjects with normal liver function, to the extent that it no longer approximates hepatic blood flow but is influenced to a greater extent by hepatic intrinsic clearance (22). By reducing first-pass hepatic metabolism, cirrhosis also may cause a clinically significant increase in the extent to which nonrestrictively eliminated drugs are absorbed.
When portosystemic shunting is present, total hepatic blood flow (Q) equals the sum of perfusion flow (Qp) and shunt flow (Qs). Portocaval shunting will impair the efficiency of hepatic extraction and reduce the extraction ratio, as indicated by the following modification of Equation 7.5 (23).
The corresponding impact on hepatic clearance is given by the following equation:
Because Q and Qp are both reduced in patients with severe cirrhosis, in whom portocaval shunting is most pronounced, hepatic clearance will be reduced more for nonrestrictively than for restrictively metabolized drugs.
Similarly, restrictively metabolized drugs exhibit little first-pass metabolism even in patients with normal liver function, so portocaval shunting will have little impact on drug bioavailability. On the other hand, portocaval shunting will decrease the extraction ratio and increase the bioavailability of nonrestric-tively metabolized drugs as follows:
For example, if the extraction ratio of a completely absorbed but nonrestrictively metabolized drug
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