Week 3 - Biopharmaceutics and Pharmacokinetics

Pn. Khadijah Hanim bt. Abdul RahmanSchool of Bioprocess Engineering

University Malaysia Perlis

Drug Clearance

• Body is considered as a system of organs perfused by plasma and body fluids.

• Drug elimination from the body is an ongoing process due to both metabolism (biotransformation) and drug excretion through the kidney and other routes.

Drug Clearance

• The mechanisms of drug elimination are complex, but collectively drug elimination from the body quantities using the concept of drug clearance.

• Drug clearance refers to the volume of plasma fluid that is cleared of drug per unit time.

• Clearance may also be considered as the fraction of drug removed per unit time multiplied by VD.

Drug Clearance

• The rate of drug elimination may be expressed in several ways, each of which essentially describes the same process, but with different levels of insight and application in pharmacokinetics.

Drug Clearance

• Drug Elimination Expressed as Amount per Time Unitmass approach:

• For zero-order elimination process- expressing the rate of drug elimination as mass per unit time is convenient- rate is constant.

Drug Clearance

• Drug Elimination Expressed as Volume per Time Unit

Clearance (volume) approach:

• First-order elimination-drug clearance expressed as volume per unit time is convenient- it is constant

• Clearance- the rate of drug removal in terms of vol. of drug sol. removed per unit time.

• Drug conc. in the body gradually decline by 1st order process- mass of drug removed over time, is not constant.

• Rate of drug removal- dependent on the plasma drug conc. at all times.

• Clearance- for 1st order process is constant. Clearance expressed in vol. per unit time rather than drug amount per unit time.

Clearance (volume) approach

Rate of drug elimination is

Dividing both side by CP

Drug Clearance

• Drug Elimination Expressed as Fraction Eliminated per Time UnitFractional approach

Fractional approach

• Consider a compartment volume, containing VD liters.

• If Cl is expressed in liters per minute (L/min), • then the fraction of drug cleared per minute in

the body is equal to Cl/VD.

Clearance and Vol. of distribution ratio, CL/VD

• Fraction of Cl/VD-dependent on - VD- Rate of drug clearance from the body• If drug conc. = Cp, rate of drug elimination (in terms of rate of change in conc.)

• 1st order process:

• Equating the 2 expressions:

• 1st order rate constant= fractional constant Cl/VD

One-Compartment Model Equation in Terms of Cl and VD

• Substituting Cp0 and k

Cp = Cp0 e-kt

One-Compartment Model Equation

• The IV single dose Equation may be modified to calculate the elimination rate constant or half-life of a drug in a patient when two plasma samples and their time of collection are known:

One-Compartment Model Equation

• If the first plasma sample is taken at t1 instead of at zero and C2 is the concentration at time t2 and t is set to (t2 — t1).

One-Compartment Model Equation

• Rearrange:

• Half-life:

Clearance from drug-eliminating tissues

• Clearance- applied to any organ involved in drug elimination.

• 1st order elimination processes involved- clearance represents the sum of the clearances for each drug-eliminating organ:

Clearance from drug-eliminating tissues

• Drug clearance considers:- Drug in body evenly dissolved in a vol. of fluid (VD).• Plasma fluid conc. measured, clearance calculated as fixed vol.

of plasma fluid cleared of drug per unit time. Unit for Cl = vol/time.

Clearance from drug-eliminating tissues

• Rearranging:

• ClT is a constant, represents the slope of the line obtained by plotting dDE/dt versus Cp

• 1st order elimination drug, rate of elimination dependent on the amount of drug remaining in the body

Clearance from drug-eliminating tissues

• Substituting the elimination rate:

• ClT = product of VD and k- both are constant• As plasma drug conc. decreases during

elimination, the rate of drug elimination dDE/dt will decrease but clearance remain constant.

Clearance from drug-eliminating tissues

• Clearance can also be determined directly from plasma drug conc. versus time curve:

• Do = dose and

Elimination half-life (t1/2) Elimination half-life (t1/2)

Definition: Elimination half-life is the time it takes the drug concentration in the blood to decline to one half of its initial value.

The elimination half-life is dependent on the ratio of VD and CL.

Unit : time (min, h, day)