Pharmacokinetics Parameters by NOVATUS CHING'ORO, MUHAS.

B.PHARM-2 (2017/2018)
novatuschingoro@gmail.com ->BPHARM
STUDENT,SOP-MUHAS
6/5/2018 1

. PHARMACOKINETICS
Presenter: NOVATUS CHING’ORO
BPHARM-2 STUDENT, SOP-MUHAS
E: novatuschingoro@gmail.com
STUDENT,SOP-MUHAS
6/5/2018 2

Presententation Contents:
Relationship between
AUC,Clearance,Elimination Constant and
volume of distribution. Worked examples on
questions involving the mentioned parameters
Creatinine clearance and its maintainance in
men and women.
Why creatinine is considered as suitable marker
for representing the kidney functioning??
STUDENT,SOP-MUHAS
6/5/2018 3

AT THE END OF THIS PRESENTATION….
1
• We should understand the mathematical relationships
between drug concentration in the plasma and time
2
• Concepts of clearance and volume of distribution, which
together determine the half‐life of a drug.
3
• We should be able to link between Renal clearance
(measured by creatinine) and drug clearance.
4
• With knowledge of clearance and distribution, we should be able to
propose or give an account on drug in relation to desirable therapeutics and
minimal toxicity.
STUDENT,SOP-MUHAS
6/5/2018 4

INTRODUCTION
PHARMACOKINETICS, PK
(ADME)
PHARMACODYNAMICS, PD
PHARMACOLOGY
STUDENT,SOP-MUHAS
6/5/2018 5

STUDENT,SOP-MUHAS
6/5/2018 6

STUDENT,SOP-MUHAS
6/5/2018 7

STUDENT,SOP-MUHAS
6/5/2018 8

PHARMACOKINETICS AND PLASMA
CONCENTRATION OF DRUG (Cp)
• Pharmacokinetics is
based on the study of
the variation of plasma
concentration of drugs .
• This is because the
concentration is easily
accessible parameter as
far as drug ADME is
concerned.
STUDENT,SOP-MUHAS
6/5/2018 9

CONT…
• This takes us to variables that relates drug
dosage and plasma as a part of central
compartment in single compartment model. This
variables are called PHARMACOKINETICS
PARAMETERS.
• Pharmacokinetics parameters these are variables
that are employed to study the variation of
plasma concentrations of drug and hence to be
able to formulate a desirable and effective
therapeutic dosage with minimal toxicity .
STUDENT,SOP-MUHAS
6/5/2018 10

PHARMACOKINETICS PARAMETERS
CONT…
• These parameters include the following:
 Clearance of the drug
 Volume of distribution
 Area under the curve (AUC) of conc.-time curve of
drug elimination phase
 Half life, Elimination and absorbtion constant
 Bioavailability and bioequivalance
 Steady state concentration.
 Dosing rate /infusion rate
 Loading dose and Maintenance dose
 etc
STUDENT,SOP-MUHAS
6/5/2018 11

1. CLEARENCE.
• Clearance is the fraction of a theoretical volume completely
purified (i.e.no longer containing any of the drug
concerned) per unit of time.
• Plasma clearance is the apparent volume of plasma
purified per unit of time.
• Total clearance (CLT) is the fraction of the volume of
distribution, Vd which is completely purified per unit of
time. The total clearance depends on the constant of
elimination and thus on T ½ and on Vd.
• Clearance is a constant in linear kinetics. Non linear ones
also present.
• NOTE: THIS IS THE MOST IMPORTANT PARAMETER AMONG
ALL. WHY????
STUDENT,SOP-MUHAS
6/5/2018 12

CONT…
• Clearance of the drug in a body can be of
individual organ.
– major-liver ( hepatic clearance, CLH)
->kidney ( renal clearance, Clr)
– Minor-> skin, lung ( often represented as Clother)
STUDENT,SOP-MUHAS
6/5/2018 13

CONT…
• The total clearance of the body is then a
summation of individual organ clearance often
of the major organs
• ie; CLT= CLH+CLR+CLOTHER--------EQ 1
NOTE: individual organ clearance (Clorgan)is
obtained as product of extraction ratio (ER or
E) of the organ and the blood volume flow
rate (Q) to that organ
STUDENT,SOP-MUHAS
6/5/2018 14

CONT…
• ie;
• CLorgn=( ER).Q
Also ER/E of the organ is obtained as:
STUDENT,SOP-MUHAS
6/5/2018 15

unitless(ratio)
• ie;
• CLorgn=( ER).Q mL/hr
STUDENT,SOP-MUHAS
6/5/2018 16

unitless(ratio)
• ie;
• CLorgn=( ER).Q mL/hr
STUDENT,SOP-MUHAS
6/5/2018 17

STUDENT,SOP-MUHAS
6/5/2018 18

STUDENT,SOP-MUHAS
6/5/2018 19

STUDENT,SOP-MUHAS
6/5/2018 20

STUDENT,SOP-MUHAS
6/5/2018 21

RENAL CLEARANCE
• It is experimentarily performed by
determining the concentration of creatinine in
urine or blood serum.
• Creatinine is end product of creatine
metabolism in muscle cell.
• It therefore differ from female and male due
to fact that muscle tissue size in male is overall
comparably larger than that of female.
STUDENT,SOP-MUHAS
6/5/2018 22

Creatine metabolism->Creatinine
STUDENT,SOP-MUHAS
6/5/2018 23

Cont…
• Normal creatinine level in male blood serum is
ranging from 0.7-1.3mg/dL
• Normal creatinine level in female blood serum is
ranging from 0.6-1.1mg/dL
• Abnornmal level of creatinine in blood serum
significantly is used to account for kidney
function inturn to link with associated conditions
like hypertension and diabetes.
STUDENT,SOP-MUHAS
6/5/2018 24

Qn; why creatinine and not
glucose……???
• Creatinine has become usefully in
determination of renal functioning as it is
suitable endogenous compound which:
• Has constant/ stable conceentration in plasma.
• Its biochemically inert to the rest of biochemical
reaction cascades.( not metabolized)
• It is not re-absorbed.
• its freely filtered
STUDENT,SOP-MUHAS
6/5/2018 25

Question to ask our ourselves!
Why do we involve renal
clearance employing
creatinine as far as drug
clearance is concerned?
STUDENT,SOP-MUHAS
6/5/2018 26

Ans….
1. drug clearance follows the same way in which
creatinine is cleared from the plasma. For
heathy human, its expected that creatinine is
continously excreted to keep it’s amount in
plasma at normal level. Similary drugs are
exogenous compounds that are to be efficiently
cleared from the plasma after their therapeutic
activity. Excessive accumulation of drug in the
body implies organ impairment. Hence leads to
increase in drug toxicity.
STUDENT,SOP-MUHAS
6/5/2018 27

Ans…..
2. Following drug elimination characteristics,
drugs are also employed as suitable
exogeneous markers to determine renal
functionig just as it is used for creatinine.
REMEMBER: The measurement can be done
using blood (serum) sample
spectrophotometery or urine by employing
suitable lab. technique.
STUDENT,SOP-MUHAS
6/5/2018 28

2. VOLUME OF DISTRIBUTION
• The volume of distribution (Vd) is the fictitious volume,
expressed in liter or in liter per kilogram, in which the drug
would have been distributed by supposing that its
concentration is homogeneous, i.e. the average tissue
concentration is identical to that of the plasma.
• It is expressed as Vd =dose/C0 (initial concentration).
• For example, after intravenous injection of 100 mg of a
drug whose initial concentration, C0, in plasma is 10 mg/L,
• the volume of distribution is of 10 L . For a given drug, the
knowledge of its desirable concentration in blood and of its
volume of distribution allows evaluation of the dose to
administer
STUDENT,SOP-MUHAS
6/5/2018 29

Cont…
• Vd Value < 0.071 L/kg (4.97L/ 70Kg) indicate the
drug is mainly in the circulatory system. Values >
0.071 L/kg indicate the drug has gotten into
specific tissues.
• Plasma binding proteins to drug decreases Vd
while increases plasma drug concentration. The
vise versa is true for tissue (out of these of blood)
which tend to bind the drug.
• Volume of distribution can vastly exceed any
physical volume in the body…..WHY???
STUDENT,SOP-MUHAS
6/5/2018 30

Cont…
• because it is the volume apparently necessary
to contain the amount of drug homogeneously
at the concentration found in the blood,
plasma, or water.
• To verify this concept, let us typically
examplify it. Consider the table below…
STUDENT,SOP-MUHAS
6/5/2018 31

STUDENT,SOP-MUHAS
6/5/2018 32

• THE TOTAL BODY WATER=0.6L/KG
• THIS IMPLIES> 0.6*70=42L/70KG
STUDENT,SOP-MUHAS
6/5/2018 33

STUDENT,SOP-MUHAS
6/5/2018 34

This is because……………
• Drug can distributes itself in several body
compartments (physical volumes) including in one or
more than either of blood,plasma,extracellural water ,
fats, muscle or bones.
• The distribution/partion extent of the drug to either of
the mentioned components of body’s physical
volumes depends greatly on the physicochemical
properties of the drug. Refer the “ Physico-chemical
grouping of drugs”.
• TAKE HOME MESSAGE “The higher the Vd of the drug,
the easier the organ clearance of the drug
is”………WHY??
STUDENT,SOP-MUHAS
6/5/2018 35

3.HALF LIFE
• The plasma half-life of a drug (T ½) is the time necessary to
halve the plasma concentration, for example to decrease
from 100 to 50 mg/L.
• The knowledge of the half-life is useful for the
determination of the frequency of administration of a drug
(the number of intakes per day) for obtaining the desired
plasma concentration.
• Generally, the half-life of a particular drug is independent
of the dose administered.
• In certain exceptional cases, it varies with the dose: it can
increase or decrease according to, for example, the
saturation of a mechanism (elimination, catabolism,
binding to plasma proteins etc).
STUDENT,SOP-MUHAS
6/5/2018 36

• Elimination normally can follow zero order or
first order kinetics. Some others follow
complex kinetics
• Under both cases,elimination constant (kel)
and half life (t1/2) are important parameters
that are to be dealt with as far as desirable
therapeutic effect (dosage) and toxicity are
concerned.
• However both zero and first kinetics differs.
STUDENT,SOP-MUHAS
6/5/2018 37

Comparison: zero and 1st order kinetics
STUDENT,SOP-MUHAS
6/5/2018 38

Comparison: zero and 1st order kinetics
STUDENT,SOP-MUHAS
6/5/2018 39

4. AREA UNDER THE CURVE.
• The area under curve, AUC, corresponds to the
integral of the plasma concentration versus an
interval of definite time.
• AUC = ƒ ([C] x Dt)
[C]: is measured concentration and
Dt: interval of time between two
measurements.
The precision of the AUC grows with the number of
measurements of concentration taken.
STUDENT,SOP-MUHAS
6/5/2018 40

AUC CONT…
• The measurement of
the bioavailability of a
drug employs this
concept.
• The larger the area the
large the bioavailability
of the drug basing on
administration routes.
STUDENT,SOP-MUHAS
6/5/2018 41

HOW TO FIND AUC.
1. By integral method
STUDENT,SOP-MUHAS
6/5/2018 42

2. The AUC can be deduced from
STUDENT,SOP-MUHAS
6/5/2018 43

STUDENT,SOP-MUHAS
6/5/2018 44

To find Co of the drug in plasma
STUDENT,SOP-MUHAS
6/5/2018 45

What does the AUC implies??
• AUC- ( Area under the plasma drug concentration
against time under drug elimination phase curve )
implies the measured concentration of drug in
systemic circulation as the function of time from
zero to infinite.
• The area under the blood concentration-time
curve (AUC) is a common measure of the extent
of bioavailability for a drug given by a particular
route .
• AUC is direct proportion to F.
STUDENT,SOP-MUHAS
6/5/2018 46

APPLICATION OF AUC.
1.Calculation of systematic clearance of drug in
the central compartment.
CL= DOSE/ AUC
Remember; unit for dose weight->mg
unit for AUC->mg.hr/ml
Thus clearance unit-> ml/hr,
generally volume per time unit!
STUDENT,SOP-MUHAS
6/5/2018 47

2. Calculation of clearance by the organ
Clorgan= (dose . F)/ AUC
3. Bioavailability to the organ
F=(AUC)organ/ (AUC)iv
STUDENT,SOP-MUHAS
6/5/2018 48

OTHER RELATIONS INVOLVING CL.
1. CL= Dosage rate/ Css
2. CL=Rate of elimination/COP
3. CL= Vd .Kel
4. CL= O.693Css/ t ½ . For first order.
5. CL=(0.693Vd)/ t1/2
STUDENT,SOP-MUHAS
6/5/2018 49

3. CL= Vd .Kel -----NOTE : t1/2=0.693/kel
5. CL=(0.693Vd)/ t1/2
STUDENT,SOP-MUHAS
6/5/2018 50

3. CL= Vd .Kel -----NOTE : t1/2=0.693/kel
5. CL=(0.693Vd)/ t1/2
STUDENT,SOP-MUHAS
6/5/2018 51

SAMPLE QUESTION #1
STUDENT,SOP-MUHAS
6/5/2018 52

#2. Determine CO, t1/2,Kel,AUC,CL,Vd
given that Do=25mg
STUDENT,SOP-MUHAS
6/5/2018 53

#3.
STUDENT,SOP-MUHAS
6/5/2018 54

#4.
STUDENT,SOP-MUHAS
6/5/2018 55

STUDENT,SOP-MUHAS
6/5/2018 56

#5
STUDENT,SOP-MUHAS
6/5/2018 57

References…
1. Lippincott - Modern Pharmacology With
Clinical Applications
2. Goodman and Gilman's
3. Katzung Basic and Clinical Pharmacology, 11E
2009
4. Online source:
STUDENT,SOP-MUHAS
6/5/2018 58

STUDENT,SOP-MUHAS
6/5/2018 59

Pharmacokinetics Parameters by NOVATUS CHING'ORO, MUHAS.

Recommended

Recommended

More Related Content

What's hot

What's hot (19)

Similar to Pharmacokinetics Parameters by NOVATUS CHING'ORO, MUHAS.

Similar to Pharmacokinetics Parameters by NOVATUS CHING'ORO, MUHAS. (20)

Recently uploaded

Recently uploaded (20)

Pharmacokinetics Parameters by NOVATUS CHING'ORO, MUHAS.