1

Single-dose kinetics

Plasma [Drug] curve

Upon administration

[drug]plasma reaches a max

Then begins to decline as the

Drug is eliminated

Cpmax =max plasma [drug]

tmax = time to reach Cpmax

AUC= area under the curve=

These measures are useful for comparing the bioavailability of different pharmaceutical formulation

59-291 Section 1, Lecture 6

2

Bioavailability- the fraction of the administered dose that reaches

the systemic circulation= AUCoral/AUCIV

AUCoral can be affected by:

-rate of tablet disintegration

-drug solubility

-sequestration by food

-gastric acid and gut

enzyme inactivation

3

Continuous and multiple dose kinetics

Steady-State Principle: for drugs exhibiting first-order pharmacokinetics

[Drug] [Drug]plasma [Drug]urine,

rate= [Drug] x kabs rate= [Drug]plasma x ke

Rate of administration or absorption

Rate of elimination

Initially rate of admin. or absorption greater than rate of elimination because initially [Drug]plasma is low

-rate of elimination gradually increases as [Drug]plasma increases

and reaches a plateau. This is termed the steady-state concentration.

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Since the time to reach steady-state is composed of 2 first-order processes, it also obeys the rules of 1st order reactions.

It takes 5 half-lives to complete a 1st order process:

(1/2n)= 1/ 2x2x2x2x2= 1/32= 0.03 or 3% remains or 97% produced after 5 half-lives

Time required to reach the steady state is independent of the drug dose and frequency of drug administration

5

Half-Life• The time it takes for one half of the original amount of a drug in the body

to be removed• A measure of the rate at which drugs are removed from the body

Dug concentration 100 50 25 12.5 6.25 3.125

Hours after peak concentration

0 8 16 24 32 40

Number of half-lives

0 1 2 3 4 5

Percentage of drug removed

0 50 75 88 94 97

6

Steady-State concentration depends on:

-drug dose/unit time; and t ½ of the drug

-if you double either, you get the same effect

7

-an intermittently administered drug will accumulate to a steady- state at the same rate as a drug given by continuous infusion BUT the fluctuations in [drug]plasma will be less with the latter method

8

Dosage Calculations;

Loading dose- dose to establish a rapid therapeutic [drug]plasma

= Vd x desired [drug]plasma dose/Cp0

In the case of toxic drugs (digitalis) Loading dose is divided into several portions and given over a long time

Maintenance dose= dose required to maintain a desired steady-state

Rate of elimination (in hours) x dosage interval in hours

At steady state: rate of elimination=rate of administration (absorption)

rate of elimination = Cl x avg [Drug]steady-state plasma

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Example for Gentamicin:

[Gentamicin]steady-state plasma= 2 mg/L

Clgentamicin=100 mL/min

rate of elimination = Cl x avg [Drug]steady-state plasma

= 0.1 L/min x 2 mg/L

= 0.2 mg/min

What is the maintenance dose for administration once every 8 h?

Maintenance dose = Rate of elimination (in hours) x dosage interval in hours

= 0.2 mg/min x 60 min/h x 8h

= 96 mg

10

Practice questions

• Define bioavailability and list the parameters that are useful for comparing different formulations– the fraction of the administered dose that

reaches the systemic circulation= AUCoral/AUCIV

– CPmax

– Tmax

– AUCoral

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• List the parameters that affect bioavailability of orally administered drugs– rate of tablet disintegration– drug solubility– sequestration by food– gastric acid and gut enzyme inactivation