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he liver is the major body site for xenobiotic metabolism, the
biotransformation of chemicals not normally present in biological
systems, such as environmental pollutants and medications. It
determines the disposition of many drugs. The plasma concentration
of unchanged drug is directly affected by the liver metabolism.
Drugs with high lipophilicity and pKa undergoes extensive first pass
metabolism, adversely affecting the therapeutic action. There are
two determinants to a drugs therapeutic efficacy, namely, its intrinsic
activity at a target and its bioavailability at the site of action. Liver
disease causes multiple pathophysiologic changes that influence
drug bioavailability. Decreased hepatic blood flow, extrahepatic and
intrahepatic blood shunting, and loss of hepatocytes alter the ability
to metabolize drugs. The bioavailability of administered medications
increases, effectively increasing the dose. Decreased protein
synthesis decreases the percentage of drug bound to plasma proteins
and increases the amount of ?free? or unbound drug. The increase
in free fraction makes more drug available to the receptor site and
more drug available for metabolism, thereby increasing its clearance.
Increased clearance does not occur if hepatocytes are not capable
of metabolizing the drug, however. An increase in free fraction and
a decrease in hepatocyte function result in an increase in free drug
concentration.There is a significant potential for liver disease to alter
the pharmacokinetics as well as pharmacodynamics of many drugs.
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