This document discusses pharmacokinetic and bioavailability variations in disease states, specifically related to hepatic disease. It defines key terms like pharmacokinetics, bioavailability, and variability. It then discusses how hepatic disease, both acute and chronic liver impairment, can interfere with drug metabolism and elimination due to changes in absorption, distribution, metabolism and excretion. Specific impacts on absorption, metabolism in the liver, enzyme induction and inhibition, as well as dosage considerations based on the fraction of drug metabolized by the liver are covered. An example calculation is provided to illustrate how a reduced hepatic clearance of 50% would impact the total body clearance and necessary dose adjustment.

1. PHARMACOKINETIC AND
BIOAVAILABILITY VARIATIONS IN
DISEASE STATES
PRESENTED BY: AYESHA AJAZ
Hamza Gulzar
Waqar Ahamd
PRESENTED TO : Dr. IKRIMA KHALID

2. DEFINITION
• Pharmacokinetics is the science of the kinetics of drug
absorption, distribution, and elimination (ie,
metabolism and excretion).
• Bioavailability refers to the extent and rate at which
the active moiety (drug or metabolite) enters systemic
circulation, thereby accessing the site of action.
• Pharmacokinetic variability which is due to difference
in drug concentration at the site of action because of
inter individual differences in drug absorption,
distribution, metabolism and excretion.

3. HEPATIC DISEASE:
Introduction:
• Acute liver impairment interferes with drug
metabolism and elimination
• Chronic liver impairment affects all parameters of
pharmacokinetics
• Most of the drugs are metabolized by liver therefore
susceptible to drug toxicity.
• Hepatotoxicity is potentially life threatening.

4. Absorption & Liver:
• Some oral drugs are extensively absorbed in
liver
• This process is first-pass effect.
• With cirrhosis, oral drugs are distributed
directly into systemic circulation.
• So oral drugs metabolized in liver must be
given in reduced doses.

5. Metabolism in liver:
• Most of the drugs are metabolized by
enzymes in liver and these are cytochrome
P450.
Drugs effect on liver:
• With chronic administration some drugs increase
metabolizing enzymes in liver called Enzyme
induction.
• Enzyme induction accelerates drug metabolism and
larger doses are required.
• Rapid metabolism increases production of toxic
metabolites.

6. • Enzyme inducers consist of phenytoin, rifampin,
phenobarbital and cigarette smoking.
Enzyme inhibition:
• Metabolism can be decreases in a process called
enzyme inhibition.
• It occurs with co- administration of drugs that
compete for same metabolizing enzyme.
• So smaller doses of slow metabolizing drugs are
needed to avoid toxicity.
• Enzyme inhibitors consist of cimetidine, fluoxetine
and ketoconazole.

7. Dosage Considerations in Hepatic
Disease:

8. Fraction of Drug Metabolized:
Drug elimination in the body may be divided into;
1. fraction of drug excretion unchanged, fe
2. fraction of drug metabolized
• The fraction of drug metabolized is estimated from 1-fe.
• Alternatively, the fraction of drug metabolized may be
estimated from the ratio of Clh/Cl, where Clh is hepatic
clearance and Cl is total body clearance.
• Drugs with low fe values (or, conversely, drugs with a higher
fraction of metabolized drug) are more affected by a change
in liver function due to hepatic disease.

9. Example:
• The hepatic clearance of a drug in a patient is
reduced by 50% due to chronic viral hepatitis.
How is the total body clearance of the drug
affected? What should be the new dose of the
drug for the patient? Assume that renal drug
clearance (fe = 0.4) and plasma drug protein
binding are not.

11. where RL = residual liver function. [Clh]normal = hepatic
clearance of drug in normal subject [Clh]hepatitis = hepatic
clearance of drug in patient with hepatitis.
[ClR]normal = renal clearance of drug in normal subject Clnormal
= total clearance of drug in normal subject Clhepatitis = total
clearance of drug in patient with hepatitis fe = fraction of drug
excreted unchanged 1 – fe = fraction of drug metabolized
• Substituting in Equation 24.44 with RL = 0.5 and fe = 0.4
• The adjusted dose of the drug for the hepatic patient is 70%
of that for the normal subject as a result of the 50% decrease
in hepatic function in the above case (fe = 0.4)

12. THANKS