Kinetics Final Exam Review

Warmup
The table below shows plasma drug concentrations for a 70kg patient after an IV bolus
injection of Drug Y (VD=0.8L/kg).
Time (hr) Plasma Concentration (mcg/mL) Forward equation

2 3.68 Cp = C0 e-kt
4 1.35
6 0.50
Reverse equation
C0 = Cp ekt
Calculate the initial dose in mg.
Calculate the plasma drug concentration 30 minutes after injection.
Find k. (ln 3.68- ln 0.5)/(6-2) = 0.5

Find C0. Use reverse equation. C0 = 3.68 e0.5*2 = 10 mg/L (mg/L = mcg/mL)
Find VD. VD = 0.8*70 = 56 L
Find D0. D0 = C0*VD = 10*56 = 560 mg (stay consistent with units for C0)
Initial dose = 560mg
Find Cp at 30min (t=0.5hr). Cp = C0 e-kt Cp = 10 e-0.5*0.5 = 7.8 mg/L

Advanced: use the reverse equation: Start at t=2hr. Desired Cp is 1.5hr before 2hr.
Cp = 3.68 e0.5*1.5 = 7.8 mg/L
Final Exam Review
Charles Dang
Final Exam
Exam 1 Exam 2 Recent Material
25% 25% 50%
Outline
Nonlinear Pharmacokinetics
Pharmacodynamics
Review Questions
Other Questions
Nonlinear
What is this showing?
a) 0th order process
b) 1st order process
c) Partially 0th order, Partially 1st order
d) IV infusion
C e) Reaching SS concentration
t
Nonlinear
1st order (rate
concentration) 0th order (rate is nearly constant)
Rate = Vmax
Nonlinear: Definition
AUC vs Dose = linear
Css vs Dose = linear
Case A = nonlinear kinetics
Case C = linear kinetics

Css or AUC
Nonlinear (whats the big deal?)
Linear (usual case): We are concerned with the Cp as a function of time.

Elimination rate = k Cp Solution:
Cp = C0 e-kt
Nonlinear: Michaelis-Menten
Cp appears in denominator Solution in terms of Cp and t
(messy, difficult to solve)
Cp appears twice, not much improvement

Nonlinear Equations
Not easy to solve!!

Cp appears on both LHS and RHS
The only equation that is straightforward

Vmax and Km
We solve only the easy cases
Cp >> Km
Drug is far to the right of Km
0th order elimination
Ethanol, salicylate, phenytoin
How many times smaller or

bigger than Km does Cp have
to be in order to use these
approximations?
Cp 10x is safe
Cp << Km
Drug is far to the left of Km
1st order elimination
k= Vmax/Km
Apply k= Vmax/Km
4. A given drug is metabolized by capacity-limited (nonlinear) pharmacokinetics.

Assume KM is 0.2 mg/mL, Vmax is 20 mg/mL per hour, and VD is 20 L/kg.
a. What is the reaction order for the metabolism of this drug when given in a
single intravenous dose of 100 mg/kg?
Cp = 100/20 = 5mg/L or 5 mcg/mL Cp >> KM 0th order
b. How much time is necessary for the drug to be 50% metabolized?
C0 = 250 mcg/mL. How long does it take to go from 500 to 250 mcg/mL?
Vmax = 20 mcg/(mL*hr) (rate of reduction in Cp)
t = (500-250)/20 = 12.5 hr
Direct equation:
t = 1/20*(500-250 + 0.2*ln(500/250)) = 12.5hr same answer!
Apply
A drug eliminated from the body by capacity-limited (nonlinear) pharmacokinetics
has a KM of 100 mg/L and a V max of 50 mg/hr. If 400 mg of the drug is given to
a patient by IV bolus injection, calculate the time for the drug to be 50%
eliminated. VD = 80L.
k= Vmax/Km
Calculate the time for 50% elimination of the dose when the dose is 10mg.
Cp = 0.125mg/L << KM Assume 1st order.

k= 50/100 = 0.5 hr-1 t1/2 = 0.693/0.5 = 1.39 hr
Using the direct equation (above) for t gives t1/2 = 1.48 hr
The 1st order approximation is close enough.
Urinary Excretion
The figure below shows urinary excretion data for a metabolite of marijuana (THCCOOH).
Find the elimination rate constant, k.

Find the excretion rate constant, ke.
What % of total clearance is nonrenal clearance ?
Urinary Excretion
Intercept gives ke (with some algebra)
Slope gives k
k = elimination rate constant

ke = EXCRETION rate constant
k represents the TOTAL elimination

k = ke + km + kl + whatever else
Kidney excretion
liver metabolism
lung excretion
k = ke + knr where nr = nonrenal

Urinary Excretion
The figure below shows urinary excretion data for a metabolite of marijuana (THCCOOH). The
dose is 500,000 mcg.
k = 0.693/30.7 = 0.023 hr-1
Intercept 3.7
log(keDB) = 3.7
keDB = 103.7 5000
DB (given) =500,000
Ke = 5000/500,000 = 0.01
Knr = 0.023 0.01 = 0.013

% of total clearance=
Clnr/ClT = (knr VD)/(k VD) =
Find the elimination rate constant, k. knr / k = 57%
Find the excretion rate constant, ke.
What % of total clearance is nonrenal clearance ?
Pharmacodynamics
Pharmacokinetics provides Cp vs time
Pharmacodynamics explores the
relationship between concentration and
the pharmacologic response.
Duration of Activity
MEC teff = duration of activity

Duration of
activity
Plasma leveltime curves describing the
relationship of both dose and elimination half-
life on duration of drug action.
Ceff = effective concentration = MEC.
VD is 10L.
Curve a = single 100-mg IV injection of drug;

k = 1.0 hr 1.
Curve b = single 1000-mg IV injection;

k = 1.0 hr 1.
Curve c = single 100-mg IV injection;

k = 0.5 hr 1.
1 C0

= ln
k Ceff

VD is 10L. Calculate teff for the following
cases. MEC = 0.1 mg/L
Curve a = single 100-mg IV injection of drug;

k = 1.0 hr 1.
teff = 4.6hr
Curve b = single 1000-mg IV injection;

k = 1.0 hr 1.
teff = 6.9hr
Curve c = single 100-mg IV injection;

k = 0.5 hr 1.
teff = 9.2hr
1 C0

= ln
k Ceff

Hysteresis == loop
@ every point on the plasma concentration curve, there is a value for effect.
e.g. effect can be the drop in body temperature upon taking ibuprofen.
The data can be regraphed, using Effect as the y-axis and Cp on x-axis.
A loopy figure results. This loop is called a hysteresis.
Hysteresis makes it look like we have two distinct processes, a forward one and one
looping back.
t=20
Loop back
Effect = 0.2
Effect = 0.6 Effect

t=48 t=6
Effect = 0.3 Forward process

t=3
t=1
Cp
Plasma compartment
Hysteresis
t=20
When considering the effect
compartment only, hysteresis
virtually disappears. t=3 t=6
Effect
The loop collapses into what
looks like a single unifying t=48
curve. This theoretically makes t=1
analysis simpler because we no
longer have to worry about what
was technically two separate
processes.
C at effect site
Effect compartment
Integrated Pharm. Response
IPR = Duration * Intensity

Intensity
IPR increases when the same dose is

divided into multiple applications.
Duration of
activity
IPR and Divided Doses
Which has greater total IPR?
Single dose (top) or
Divided doses (bottom)?
The sum of IPR

from divided doses
is bigger than that
of a single dose.
The total dose is
the same in both
cases.
Additional problems
Review Questions:
http://www.mediafire.com/?478t7hntt75hl05
Do end of chapter problems and selected in-chapter

problems.

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Warmup

Time (hr) Plasma Concentration (mcg/mL) Forward equation

Find k. (ln 3.68- ln 0.5)/(6-2) = 0.5

Find Cp at 30min (t=0.5hr). Cp = C0 e-kt Cp = 10 e-0.5*0.5 = 7.8 mg/L

Exam 1 Exam 2 Recent Material

25% 25% 50%

Case A = nonlinear kinetics

Case C = linear kinetics

Linear (usual case): We are concerned with the Cp as a function of time.

Cp appears twice, not much improvement

Not easy to solve!!

The only equation that is straightforward

How many times smaller or

4. A given drug is metabolized by capacity-limited (nonlinear) pharmacokinetics.

Cp = 100/20 = 5mg/L or 5 mcg/mL Cp >> KM 0th order

b. How much time is necessary for the drug to be 50% metabolized?

Cp = 0.125mg/L << KM Assume 1st order.

Find the elimination rate constant, k.

k = elimination rate constant

k represents the TOTAL elimination

k = ke + knr where nr = nonrenal

k = 0.693/30.7 = 0.023 hr-1

Knr = 0.023 0.01 = 0.013

MEC teff = duration of activity

Curve a = single 100-mg IV injection of drug;

Curve b = single 1000-mg IV injection;

Curve c = single 100-mg IV injection;

Curve a = single 100-mg IV injection of drug;

Curve b = single 1000-mg IV injection;

Curve c = single 100-mg IV injection;

Effect = 0.6 Effect

Effect = 0.3 Forward process

IPR = Duration * Intensity

IPR increases when the same dose is

The sum of IPR

Do end of chapter problems and selected in-chapter

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