Pharmacokinetics of Elimination

Question 1

Clearance

Answer 1

Theoretical definition: The volume of plasma (Vd) which is completely cleared of drug in a given period of time.

Formula: CL= Vd * Ke
where Ke is the fraction of total drug that is eliminated per unit time.

Clearance is best thought of as a proportionality constant that makes the average plasma concentration at steady state equal to the rate of administration (maintenance dose per dosage interval- tau:
Maintenance dose/tau= CL * Cp(ss)
-or- CL= (MD/tau)/Cp(ss)

Clearances from each organ of elimination are additive; clearance from kidney and liver are most important for most drugs.

• Hepatic Clearance:
• varies with blood flow to the liver, protein-drug binding, and instrinsic hepatic metabolic activity (coadministered by inducers and inhibitors)
• –> if metabolism IS NOT efficient, changes in hepatic blood flow do not sifnificantly influence clearance.
• —> if metabolism IS VERY EFFICIENT, changes in hepatic blood flow will have a major influence on total body clearance
• Renal Clearance:
• varies as kidney function varies (creatine is used as a measure of kidney function.
• Changes in renal function will alter clearance of renally eliminated drugs and necessitate dose changes to prevent drug accumulation.

Question 2

Half Life (t1/2)

Answer 2

Time for elimination of drug from plasma (4-5 half lives)
Time to read steady state plasma drug levels following multiple doses (4-5 half lives)
Fluctuation in plasma levels between doses (number of half-lives in dosing interval)

Question 3

Elimination rate constant (Ke)

Answer 3

Ke is the fraction of drug leaving the body per unit time via all elimination processes.

T1/2= 0.693/Ke

Question 4

First-order kinetics

Answer 4

The rate of elimination (mg/hr) is proportional to the concentration of the drug in the plasma (mg/L).

• -> Thus, as the drug is eliminated from the body, its concentration is changing, changing its rate of elimination.
• -> Most clinically utilized drugs are eliminated by first order kinetics when given in doses within the therapeutic dose range

Question 5

Zero-order kinetics

Answer 5

Rate of elimination of drug from the body is independent of the amount of drug in the body. The amount of drug removed per unit time is constant.

• Most often occurs due to saturation of hepatic metabolic enzyme systems by drug administration.
• Drugs eliminated by zero order kinitecs do not have half lives, small changes in dose can produce large changes in plasma concentration and subsequent toxicity.