Pharmacokinetics lecture 10 Contents ...

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Pharmacokinetics lecture 10Contents ...

• Extravascular administration
• Determination of bioavailability
• for extravascular doses

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Extravascular administration

• Any route other than i.v.
• An absorption stage will be involved
• Bioavailability may not be 100
• Principally oral but also intramuscular,
  subcutaneous etc

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Ka
K
Aa
Ab
Body
Rate of change in body load Input -
Output Ka.Aa - K.Ab
Gut
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Extravascular administration
Almost pure elimination
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Changing Ka
3h-1
Reduced Ka (Slower release) causes peaks to be
lower and shifted to the right.
0.4h-1
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Determination of F for extravascular doses
Assume the same dose of a drug is administered on
two occasions to the same individual. Either
different dosage forms or routes of
administration are used on the two occasions.
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Determination of F
AUC F.D rearranges to D AUC
Cl
Cl F
Drug administered on two occasions
... D1 AUC1 D2
AUC2 Cl1 F1
Cl2 F2 Dose and clearance will be same on
both occasions D1 D2 so AUC1 AUC2
and F1 AUC1 Cl1 Cl2 F1
F2 F2 AUC2
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Absolute bioavailability
Absolute bioavailability can be calculated if one
of the doses is an i.v. injection. Say the other
dose is oral ...
Foral AUCoral Fiv AUCiv Fiv is
always 1.0, so Foral AUCoral
AUCiv
Absolute oral bioavailability
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Relative bioavailability
If neither of the doses is an i.v. injection, we
can only calculate a relative bioavailability.
If we give the same dose orally and by i.m.
injection ... Foral AUCoral Fim
AUCim
This term is the bioavailability of the oral dose
relative to the i.m. dose.
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i.v.
Oral
AUCoral Absolute oral bioavailability AUCiv
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Capsule
Tablet
AUCtablet Bioavailability of tablet
AUCcapsule
(Relative to capsule)
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Practical methods for determining AUC

• For an i.v. dose can use AUC F.D

Cl

• For extravascular doses there is no
• simple formula. Have to use graphical
• methods.

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Trapezoidal rule
Verticals dropped from each point. Points
joined by straight lines. Divides
the area into a series of 6
trapezoids. Total area of
the trapezoids
gives a good
approximation of
the AUC up to the
last blood sample.
Conc
1 2 3 4 5 6
Time
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Area of each trapezoid
C2 C1
Mean height C1 C2
2 Width t2 - t1 Area C1 C2 x
(t2 - t1) 2
t1 t2
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Area of the tail
True AUC0- should include the tail area beyond
the last actual measured concentration. Calculate
as Tail Final measured conc
K
1.5 1.0 0.5 0.0
Conc
0 6 12
Time (h)
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An example -Determination of absolute oral
bioavailability
10mg of a drug have been administered on two
occasions to the same subject. One dose i.v.,
one oral.
Plan
1 From i.v. data, get clearance and AUCiv 2 From
oral data, get AUCoral up to last blood sample 3
Semi-log plot of oral data to get K and area of
tail 4 Get total AUC oral 5 Get F as AUCoral /
AUCiv
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1 Determine clearance and AUCiv
(Not dealt with in detail, as already covered in
Lecture 6.) Assume Clearance found to be 50
L/h.
AUC F.D Cl AUC 1.0 x 10mg
50 L/h 0.2 mg.h.L-1
200 µg.h.L-1
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2 Use trapezoidal rule to get oral AUC0-12h
Data from oral administration
Time (h) Conc (µg/L) 1
9.6 2 11.0 4 12.0 6 9.4
8 5.0 10 2.5 12 1.25
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Trap AUC --------------------------------------
--------------------------- 1 (0 9.6) / 2
x (1 - 0) 4.8 µg.h.L-1 2 (9.6
11.0) / 2 x (2 - 1) 10.3 3 (11.0
12.0) / 2 x (4 - 2) 23.0 4 (12.0 9.4)
/ 2 x (6 - 4) 21.4 5 (9.4 5.0) / 2
x (8 - 6) 14.4 6 (5.0 2.5) / 2
x (10 - 8) 7.5 7 (2.5 1.25) / 2 x
(12 - 10) 3.75

----------------------------------- Total
85.15
µg.h.L-1
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3 Tail area

• Tail area can be calculated from
• Tail Final conc
• K
• Final conc is the last measured
• concentration.
• To get K, need semi-log plot of data

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Not C0, but can be used to get t-half (85 µg/L)
50 30 10 5 3 1
By the later times, absorption is virtually
complete and we are seeing almost pure
elimination. Identify the terminal linear
portion, extrapolate back to zero time and get
elimination half life.
42.5 µg/L
Conc (µg/L)
t ½ 1.9 h
0 2 4 6 8 10 12
Time (h)
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Area of tail
K 0.693 t½ 0.693 1.9h
0.365h-1 Tail Final conc
K 1.25 µg/L 0.365h-1
3.42 µg.h.L-1
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4 Total AUCoral
Total area AUC0-12h Tail
85.15 3.42 µg.h.L-1 88.57
µg.h.L-1
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5 Absolute oral bioavailability
F AUCoral AUCiv 88.57 µg.h.L-1
200 µg.h.L-1 44.3
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Terms with which you should be familiar ...

• Absolute bioavailability
• Relative bioavailability
• Trapezoidal rule
• Tail area

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What you should be able to do

• Describe and explain the characteristic shape of
  the graph of concentration versus time following
  an extravascular dose.
• Describe and explain the changes in this graph if
  a slow-release dosage form is used.
• Describe the distinction between an absolute and
  a relative bioavailabilty.
• 
  Continued ...

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What you should be able to do (continued)

• Calculate AUC0- from a series of timed blood
  samples following an extravascular dose.
• Calculate bioavailability from a a pair of AUCs