Effect of dosing on duration of drug

action can be dramatic if absorption

is not fast in comparison with
elimination.

At low doses the drug effect
appears quite late and lasts only a
short time. Larger doses bring
about an earlier appearance of the
drug effect, and last substantially
longer.
Repeated drug administrations
The goal of therapeutics is to maintain the drug concentration above
the threshold level for effectiveness (C
ther
) and below the toxic
concentration (C
tox
). This can be accomplished by multiple dosing
strategies. An initial loading (or priming) dose can be used to more
rapidly achieve C
ther
, with maintenance doses given at regular
maintenance intervals
Bioavailability: The percentage of a drug that enters the systemic
circulation in an unchanged form after administration.
Bioequivalence: Comparable bioavailability between related drugs.
Therapeutic equivalence: Comparable clinical effectiveness and
safety between similar drugs.
Some definitions
Measurements of bioavailability
2. Plasma concentration measurements:
after a single oral dose of drug, serial
plasma measurements are made,
yielding: 1) peak drug concentration; 2)
time to peak concentration, and 3) area
under concentration-time curve (AUC).
AUC reflects the extent of absorption.
Bioavailability = AUC (oral) / AUC (i.v.)
1. Correlation of drug dose with
pharmacological response: possible
only for drugs with endpoints that can
be readily measured (eg.
anticoagulation by warfarin).
3. Urinary excretion: For drugs largely
excreted unchanged in the urine,
bioavailability can be determined by
urine collection. Drug formulations X
(100% bioavailability) and Z (<100%
bioavailability) have the same rate
constants of absorption but Z has a
smaller AUC and a lower total urine
accumulation. X and Y (also 100%
bioavailability) have identical plasma
AUCs and cumulative urine
accumulation.

Question: How would a first pass effect
affect these kinds of measurements?
Factors affecting bioavailability of orally administered drugs
1. Formulation of drug
product: factors include
tablet disintegration time or
dissolution time
2. Interactions with other
substances in GI tract: ion
neutralization, complex
formation, coprecipitation
(eg. mineral oil taken as a
laxative can dissolve highly
lipid-soluble drugs,
impairing their absorption).
3. Biotransformation in
intestinal mucosa or liver
(first-pass effect): see
figure at right
Drug Clearance: the quantitative basis of dosage
Clearance is the quantitative measure characterizing the rate of
removal of endogenous or exogenous substances, including
drugs, from the body or a specific portion of the body.
Routes of drug elimination
1. hepatic biotransformation
2. kidney & bile excretion
3. exhalation
4. fecal excretion
Clearance is expressed as the volume of body
fluid from which a drug is removed per unit time.
Clearance can be expressed as the product of the
first order rate constant of elimination and the
apparent volume of distribution
Cl = kV [mL/min] = [min
-1
] x [mL]

Clearance is inversely proportional to the area under a curve
(AUC) of concentration readings obtained at different times. If a
drug is completely absorbed following its administration (eg.
after i.v. injection) then
Cl = Dose / AUC [mL/min] = [mg] / [(mg/mL) x min)]

When only a fraction (F) of the dose is absorbed then
Cl = F x Dose / AUC
For measuring the AUC, the
concentrations should be plotted
on a linear not logarithmic scale
and the AUC refers to the
complete area under the curve
from time zero to infinity.
Assume a drug is administered at a constant rate (Q), in units of
amount/unit time, by intravenous infusion. The amount of drug in the
body is VC where V is the volume of distribution and C is the
concentration in the plasma. The fraction of this amount that is being
removed per unit time is given by the elimination time constant k.
Therefore the amount eliminated per unit time is kVC.
At a steady state, the rate of drug input
equals drug output and thus
Q = kVC
ss
where C
ss
is the steady
state concentration in plasma.

In terms of clearance, Q = Cl x C
ss
[mg/min] = [mL/min] x [mg/mL]


Since an immediate effect is desired, a loading dose (L) of the
drug is rapidly administered to fill body stores and establish C
ther
.
At steady state the amount of drug in the body is VC
ss
= L
Example: Assume we are about to give a drug to a 70 kg man and that
for this drug C
ther
= 2 mg/L, t
1/2
= 80 min, and his body is 70% water.
What is k? 0.693 / 80 = 0.0087 min
-1
What is V? 0.7 L/kg x 70 kg = 49 L
What is Q? Q = kVC
ss
= 0.0087 min
-1
x 49 L x 2 mg/L = 0.85 mg/min
What is Cl? Cl = kV = 0.0087 min
-1
x 49 L = 0.43 L/min
What is L? L = VC
ss
= 49 L x 2 mg/L = 98 mg