Volume of Distribution

The volume of fluid that "appears" to contain the amount of drug in the body (based on the plasma concentration).

Partially determines the relationship between dose and plasma concentration

Defines the volume of fluid that must be processed by organs of elimination

Roughly describes "tissue penetration"

May not equal an actual physiologic space.

Equation(s)

One compartment plot (Figure)

Cp0 is the plasma concentration at time = 0 (IV adminsitration ONLY)

Units

Liters or milliliters describing whole animal

Liters/kg or milliliters/kg

Figure 4.  100 mg of a drug is added to a 10 liter fish tank filled with water.  A sample is taken after equillibrium is reached.  The chemical properties of the drug control its "attraction" to the glass.

Figure 5. 100 mg of a drug (different drug than figure 4 above) is added to a 10 liter fish tank filled with water.  A sample is taken after equillibrium is reached. The chemical properties of the drug control its "attraction" to the glass.

Clearance

The volume of plasma water cleared of the drug during a specified time period.

Equation(s):

Organ clearance is calculated by determining the flow (Q) and the efficiency of extraction

Total body clearance (Clt) is the sum of all organ clearances

Experimentally we determine clearance by determining the Volume of distribution and the elimination rate constant (Figures 5-7)

Units:

Volume / unit time  (l/hr, l/min, ml/hr etc) describing whole animal

Volume / kilogram / unit time  (l/kg/hr, ml/kg/min etc.)

Rate constant of elimination

The fraction of the volume of distribution cleared per unit time (or)

The slope of the natural log plot of the drug concentration versus time profile (Figure)

Equation(s)

"Produced" by the relationship between the volume of distribution and the total clearance:

Determined from the slope of the "elimination portion" of the drug concentration vs time profile (curve).

Units

/hr, /min, hr^-1, min^-1

Figure 5.  Determining the "pharmacokinetics" of the fish tank.

Figure 6. Arithmetic plot of dye concentrations versus time. (lz = 0.0693 hrs-1,  Vz =1 l/kg, Dose =    100 mg,  T1/2 = 10 hrs, Clt = 0.0693 l/kg/hr).

Multiply the concentration by the Vz (Cp X Vz) to determine the amount in the body at each time point. Subtract the amount in the body at one time point from the amount in the body at the PREVIOUS time point to determine the amount eliminated during the time "interval."

Figure 7. Semi-Logarithmic plot of dye concentrations versus time. (lz = 0.0693 hrs-1,  Vz =1 l/kg, Dose =  100 mg,  T1/2 = 10 hrs, Clt = 0.0693 l/kg/hr).

Although the amount eliminated from the body is less and less for each time interval, the FRACTION of the amount eliminated during each interval is constant. This is demonstrated by the semi-log plot.

Elimination half-life

The time for elimination of one half of the total amount in the body.

Units

Hours or minutes

Application(s)

Tissue Residues

At 5 x T1/2 97% has been eliminated

Make sure you use the longest half-life (gentamicin example)

Metabolites may be more important than the drug

Extremely slow absorption from injection site may be the primary cause of residues.

Approach to steady state

Steady state exists when defined plasma concentrations (peak, average, trough) are identical following each administered dose during chronic therapy.

At 5 x T1/2 concentrations are 97% of steady state values no matter what the dose and interval.

Digoxin, maximum effects of digoxin may appear as late as 8 days after therapy is initiated

The relationship between dose interval and half-life determines the need for a loading dose.

A loading dose is an initial dose of drug given to shorten the time to reach the steady-state concentrations.

Figure 8.  Approach to steady state.  The figure represents a hypothetical situation in that the dose interval equals the drug half-life.

Fraction of dose absorbed (F)

When a drug is administered by any route OTHER than IV, it is rare that the entire dose is absorbed

Oral

Destroyed in GI tract, passes out in feces before it is absorbed, binds to ingesta, etc.

IM

Hydrolysis of drug in tissue, drug binding to injection site, abcess formation, etc.

Units

Either percentage of dose or fraction of the dose (59% = 0.59)

Application

The fraction of the dose absorbed determines a drug's bioavailability (how much gets into the blood stream).  Bioavailability is a common measure used to compare two different drug formulations (tablets vs. elixir) or to compare products sold by two different manufacturers (trade name drugs vs. generics).

Bioequivalence

Two drug products are bioequivalent if the nature and extent of therapeutic and toxic effects are equal following administration

Although similar and related, equal bioavailability (F) does not guarantee bioequivalence.

Figure 9. Two dose forms of the same drug are depicted. These two dose forms have equal bioavailability and they are bioequivalent.

Figure 10. Two dose forms of the same drug are depicted. These two dose forms have equal bioavailability but they are NOT bioequivalent.