Pharmacokinetics

Exam I Review

Charles Dang
 Outline
Essentials
Ch 3 Single Compartment (IV Bolus)
Ch 4 Multi Compt (IV Bolus)
Ch 5 IV Infusion
Ch 6 Clearance
Questions
 Exponentials
Describes 1st Order Processes
Mostly deal with decay/elimination here
Value at time

Cp log Cp Cp = C0 e-kt

Value at t=0

k = rate constant or
t t
elimination constant
 Warm-up
C = 100 e-0.693*t/5
What is rate constant?
0.693
100
0.693/5 For this class, k is always positive
-0.693/5

What is concentration at t = 10?

100
50
25 Alt: t1/2 = 5 t=10 is 2 half-lives k = 0.693/t1/2
10 t1/2 = 0.693/k
 Estimating t1/2
t [hr] Cp [mg/L]
Find k 0 100 Find k
From log slope eqn
Then t1/2
1 76 From ln slope eqn
2 60
Then t1/2
3 40
5 25
10 6

k= - 2.3 log(100)-log(6) k= ln(100)-ln(6)

0-10 10-0

t1/2 = 0.693/k t1/2 = 0.693/k

t1/2 = 2.47 hr t1/2 = 2.47 hr

Same answer, but simpler

Estimating t1/2
t [hr] Cp [mg/L]
0 100
1 76
2 60 60 is almost twice 25
3 40 Time difference is t1/2
5 25 t1/2 = 3 hr
10 6

Find t1/2 by eye

Then k
Estimating t1/2
t [hr] Cp [mg/L]
0 100 How about 100 and 50?
1 76 50 does not appear on
2 60 Table, so we estimate
3 40 at time 2.5hr, Cp=50
5 25 Time difference is t1/2
10 6 t1/2 = 2.5 hr

Find t1/2 by eye

Then k
Estimating t1/2
t [hr] Cp [mg/L]
0 100 Look at 100 and 25
1 76 They are related by 4x
2 60 How many half-lives is that?
3 40
5 25
Ans: 2 t1/2
10 6
Time diff = 5hr
So t1/2 = 2.5 hr

Find t1/2 by eye

Then k

k = 0.693/t1/2
 Estimating t1/2
Find k t [hr] Cp [mg/L]
0 85 Find k
Fro log slope eqn
Then t1/2 2 54 From ln slope eqn
4 35 Then t1/2
8 13

54 is ~4x 13
Calculate t1/2 and k 2 half lives or 6h in between
Using any method 1 half-life is 3h

k= 0.235
t1/2 = 2.95 or 3h Find t1/2 by eye
Then k
 Graphing
t [hr] Cp [mg/L]
0 85
2 54
4 35
8 13
100

10

1
0 2 4 6 8 10
 Graphing t [hr]
2
3
Cp [mg/L]
43
35
5 24
8 13
12 7
16 4
100
k = 0.17
t1/2 = 4.1h

Intercept
C0 = 60

10

Cp = 60 e-0.17t

1
2 4 6 8 10 12 14 16
 Calculating C0 t [hr]
2
3
Cp [mg/L]
43
35
5 24
8 13
12 7
How to back calculate the initial value?
16 4

ugly k = 0.17
t1/2 = 4.1h
ugly

Recall Cp = C0 e-kt
Flip the Cs, take away the (-)

C0 = Cp ekt Ex1: C0 = 43*e(0.17*2)

= 60.4
Ex2: C0 = 35*e(0.17*3)
= 58.3
Calculate
Find
k
t1/2
C0

Ans
k = 0.693 hr-1
t1/2 = 1hr
C0 = 5 mg/L
 1st Order Drugs
Vast majority of drugs are 1st order
Rate constant k,
half life t1/2
Straight line on semilog plot

Exceptions (Zero Order):

Alcohol
Aspirin
Phenytoin
 Single-Compartment (Ch3)

Whats happening here?

Single Bolus IV into the body.

No further addition of drug.
Hence, drug amount will only decrease from time 0.

DB = Drug in the body. DL, D0, D, dose all the same measured in mg, mcg

VD = Volume that contains the drug

in other words, volume of the compartment
 Single-Compartment (Ch3)

Whats included in this compartment? Everything!

Plasma (Blood)
Kidneys
Liver
Lungs
Skin
Muscle etc
 Single-Compartment (Ch3)

Keep in mind:

Plasma (Blood)
Fast Kidneys
Distribution Liver
Lungs
Skin
Slower Muscle
Distribution Bone
Hair
 Volume of Distribution, VD
VD can tell you where the drug is located
Compare to Blood Volume (5-8L)

VD < BV indicates drug is bound to carrier

proteins in blood, or resides in small regions
VD ~ BV drug resides in plasma
VD ~ 30-40L drug tends to reside in plasma and
tissue
VD ~ 100L drug has great distribution
throughout body
 Volume of Distribution, VD
The most common VD is measured at t=0.
Volume = Drug mass/Concentration
VD = D0 / C0
D0 is the amount of drug given (in mg or mcg)
C0 we know how to calculate (or its given)
 What can you do with VD
Besides getting a clue where drug resides,
VD can provide us clearance

Clearance is removal of fluid containing

drug
CL = kVD
CL = k D0/C0
 Clearance
t=1 removed 4 units drug

Body
t=2 removed 3 units drug

t=10 removed 1 units drug

How do we describe how quickly the drug is removed from the body?
Can calculate k but we dont always want to take a blood sample

From the urine!

Notice, however, that the concentration or drug amount removed in each
Urine sample is less and less

But the clearance (k*VD) is a constant no matter how large your sample
Calculate

Find
k, t1/2, C0
D0, VD, CL

Ans
k = 0.693 hr-1
t1/2 = 1hr
C0 = 5 mg/L
D0 = 1000mg
VD = 200 L
CL = 139L/hr
 Urinalysis
Based on the assumption that the primary
mode of elimination of drug is through the
urine
Potential errors:
Drug can be biotransformed in liver
Breathed out in lungs
Perspired
Removed through stool
 Urinalysis
Use urine data to get k
By average rate method
By sigma-minus method
 By average rate

If we did not collect the hidden data, can we still get k, t1/2 ? Yes!!

Average time elapsed Drug removal rate in urine

Find k from these two columns

From third and fourth data points, k=0.627, t1/2 = 1.1
From 1st and last data points, k = 0.682, t1/2 = 1.01
 By Sigma Minus

If we did not collect the hidden data, can we still get k, t1/2 ? No

Add up Du: 984 An estimate of drug amount

in the body
k = 0.77, t1/2 = 0.9 hr ~ DB
Multiple-Compartment (Ch4)

When even your semilog graph is not linear

You need to introduce more compartments

Initial distribution phase, followed by

Elimination phase

Do they operate sequentially? Simultaneously?

Simultaneous Distr and elim happen

At the same time. Hence the math model is:

Plasma concentration = Distribution + Elimination

 Two compartment

Plasma Muscle
Kidneys Skin
Liver Bone
Lungs Hair

Fast Distribution Slow Distribution

Can sample Cp Tissue biopsies very invasive
 Residuals/Feathering
Plug t into
Time (hr) Plasma Beta equation Alpha Part = Cp - Beta
Beta = Be -bt
Concentration
(mcg/mL) Beta Part Alpha Part
0.25 43 14.33 28.67
0.5 32
1 20 12.24 7.76
1.5 14
2 11
4 6.5
a = 1.74
8 2.8
A = 44.3
12 1.2
16 0.52
C0 = A+B = 59.4 mcg/mL

Get data for Beta Part Be familiar with

b = 0.210 These calculations
B = 15.1
IV Infusion (Ch5)

Steady State
What goes in =
What goes out
How long to reach SS

When we say we have reached SS,

We really mean we are 95% or 99% there

If IV drug infusion is increased from 100mg/hr

to 200 mg/hr, do we reach SS faster?
 Definitions
Css = Concentration at Steady State
R = infusion rate (mg/kg/hr) or just (mg/hr)
DL = Loading Dose
 Loading Dose

Do we really want to wait 4x t1/2 to reach D = no loading dose

The desired Css? C = DL too small
Sometimes not.. Especially if half life is hours A = DL too big
We introduce Loading Dose to get there quicker B = DL just right
Ideally, we reach Css instantly!
 Ch 5 Formulas

R
k
VD
 IV Infusion + IV Bolus

Concentration in Plasma
mcg/mL
(g/mL)
Time Single IV Constant
(hr) Dose (1 IV Infusion
Patient is 75kg.
mg/kg) (0.2 mg/kg
per hr)
What are we given, or what can we get quickly?
R, BW, C0
R = 15mg/hr
0 10 0 C0 = 10 mg/L
2 6.7 3.3
4 4.5 5.5 What is Css?
6 3 7 Css ~ 10 mg/L
8 2 8
10 1.35 8.6
12 9.1
Is this loading dose appropriate for the infusion?
18 9.7 Yes, C0 = Css
24 9.9
 IV Infusion + IV Bolus

Concentration in Plasma
mcg/mL
(g/mL)
Time Single IV Constant R = 15mg/hr
(hr) Dose (1 IV Infusion
Patient is 75kg. C0 = 10 mg/L
mg/kg) (0.2 mg/kg Css = 10 mg/L
per hr)
Find k, t1/2, VD, CL k=0.20
0 10 0
t1/2 = 3.46
2 6.7 3.3 VD = 7.5L
4 4.5 5.5 CL = 1.5 L/hr
6 3 7
8 2 8 What is Cp at 4h with infusion and Loading Dose?
10 1.35 8.6 10 mg/L
12 9.1
18 9.7 With infusion only, what is Cp 4h after infusion stops?
24 9.9
4.5 mg/L
 Clearance (Ch6)
For 1st Order drugs:
Volume Clearance (L/hr) is a constant
Drug Clearance (mg/hr) is not constant

Know how to use the pH, pKa equations

for weak acids and weak bases
 Zero Order
y = mx + b !!

Rate constant k has different units

Not the same as 1st order k-value
half-life is not constant
 Thanks to

Ty Huynh Christina Pamela Joshua

Crowley Charukulvanic Hurcomb

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Questions?