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Clearance Concept



   Anas Bahnassi PhD RPh
Lecture Objectives
After the completion of this lecture the student
should be able to:
1. Define clearance and extraction ratio and describe the relationship
   between them.
2. Distinguish clearance from elimination rate and elimination rate
   constant.
3. Explain the dependence of elimination half life on apparent
   volume of distribution and clearance
4. Calculate area under the plasma drug concentration versus time
   curve by use of the trapezoidal rule and by other methods
5. Calculate a patient’s creatinine clearance using the appropriate
   equation
6. Calculate dosing adjustments of a renally excreted drug in
   patients with various degrees of renal impairment (dysfunction).
A Physiological Approach to
Understand Clearance
Concept                                        Site of
                                               Action



                                                          Heart
            Clearing Organ
                                                         (Pump)
            (Kidney/Liver)




                              The blood exiting the eliminating
                             organ has a lower concentration
                             than the blood entering the organ.
                                The efficiency of Removal is
                              quantified by the Extraction Ratio
                                             [ER].
Extraction Ratio
  Extraction Ratio can be defined
as the proportion of drug removed
during passage through the organ.



   Ca
   Cv




                ������������ − ������������
         ������������ =
                    ������������
Clearance
                     A proportionality constant describing
                           the relationship between a
                         substance’s rate of elimination
                    (amount per unit time) at a given time
                     and its corresponding concentration
Clearance             in an appropriate fluid at that time.

    is:                      The hypothetical volume of blood
                                (plasma or serum) or other
                              biological fluids from which the
                               drug is totally and irreversibly
                                  removed per unit time.’

  Organ clearance = Blood flow rate X Extraction ratio
                     ������������ = ������. ������������
Hepatic
                                 Types of Clearance
  Clearance            Renal
                     Clearance

                                            The clearance of drug (a
         Metabolic                        fraction of total clearance)
         Clearance                        for a drug that is removed
                                                from the blood
   This is the total of every                 (plasma/serum) by
 individual organ clearances                  the process of renal
    that contribute to the                         excretion.
     elimination of drugs.
However, the organ clearance
    that can be routinely
determined independently in
  humans is renal clearance          ������������������������������������������ = ������������������������������������������ + ������������������������������ ������������������������������
because this is the only organ
   for which we can easily
  determine an elimination
              rate.
Clearance is a proportionality constant that relates rate
 of elimination (rate of excretion in renal clearance) to
   Plasma (or serum) concentration at any given time


              ������������������
                       ������ =   ������������������ ������������        ������
               ������������

               ������������
                       ������ =   ������������ ������������     ������
               ������������

                       ������������ = ������������
Elimination half-life
             vs. Clearance
                               0.693
     ������������ = ������������         ������½ =
                                 ������

                    0.693������
              ������½ =
                       ������������

 Elimination half life is dependent on the
volume of distribution and total clearance
Calculating Clearance

                                ������������������
     IV Bolus                              ������ =    ������������������ ������������      ������
                                 ������������

               Clearance for the entire dose can be
            obtained by integrating the right hand side
                 of the equation from t=0 to t=


            ������=∞   ������������
                          ������������     ������������������������������ ������������������������������������������������������������������ (������������������������)
                   ������������
������������ ������ =                      =
                    ������. ������������     ������������������������������ ������������������������ ������������������������������ ������ℎ������ ������������������������������
            ������=0
Calculating AUC
        IV Bolus
s




                 ������+������ ������
        Area =     2




          ������
                    ������




               ������
Calculating AUC
               Trapezoidal Rule:
                                C1 or concentration1
                                   C2 or concentration2




t1 or time1
                  t2 or time2
          Area = ((C1 + C2)/2)(t2 – t1)
������=∞                                  Calculating AUC
              ������. ������������           Trapezoidal Rule:
  ������=������
                                          C1 or concentration1
                                             C2 or concentration2




                          t1 or time1      t2 or time2
   ������=∞

              ������. ������������   = Area = Sum individual trapezoids
������=������������������������                     =(((C1 + C2)/2)(t2 – t1))
������=∞

        ������. ������������
                                      Calculating AUC
������=������              Trapezoidal Rule:

                                        C1 or concentration1
                                             C2 or concentration2

                                                                    ∞
                                                                ������������������������������������������




                                                                                 
         t1 or time1                      t2 or time2
        ������=∞
                          ������������������������ ������������������������������������������������������������������������������
                ������. ������������ =
    ������=������������������������
                                          ������
Creatinine Clearance
Creatinine clearance (Clcr) is renal clearance (Clr) applied
to endogenous creatinine ( a product of muscles
metabolism). It is used to monitor renal function and is a
valuable parameter for calculating dosage regimens in
elderly patients or those suffering from renal dysfunction.

Normal creatinine clearance (Clcr) values are:

• Adult males: 120±20mLmin-1
• Adult females: 108 ±20mLmin-1.
Creatinine Clearance
Direct measurement of Creatinine clearance



                              Rate of
              ∆������������          Creatinine
                             Excretion
               ∆������
������������������������   =
             (������������ )������������
                           Creatinine Serum
                            Concentration
Creatinine Clearance
                Indirect measurement of Creatinine clearance


Males:
                 ������������������������ℎ������(������������) × (140 − ������������������ )
    ������������������������   =
                       72 × ������������ ������������ (������������%)

Females:
                  ������������������������ℎ������(������������) × (140 − ������������������ )
������������������������   = 0.85
                        72 × ������������ ������������ (������������%)
Creatinine Clearance
            The significance of Creatinine clearance



1. Normal Creatinine clearance usually indicates normal
   kidney function
2. Creatinine clearance changes with age, physiological
   states, or other medical conditions and dose need to
   be changed accordingly
3. Dose frequency can be changed instead of changing
   the dos amount.
4. Changes in Creatinine clearance cause pharmacokinetic
   parameters to change.
Question 1
                    The table shows the concentration data vs
Time   Cp (ug/mL)
                    time for Cinoxacin after IV bolus
(hr)                administration. Plot the data and use the
                    graph to obtain the followings:
0.25   11.6±1.3
                    1. Elimination half-life (t½)
0.5    8.4±1.0      2. Elimination rate constant (k)
0.75   7.2±1.1      3. Apparent volume of distribution
1      6.1±1.1      4. Systemic clearance (Cls)
1.5    4.2±1.0      5. ∞������������������
                        0
2      3.2±0.9      6. Urine samples over 24 h showed the
                       percentage of the administered dose
3      1.9±0.7
                       recovered unchanged was 50.1%. The rest
4      1±0.4           were metablolites. Determine the renal
6      0.3±0.2         clearance (Clr), metabolic clearance (Clm),
8      0.09±0.1        the excretion rate constant (Ku), and the
                       metabolite rate constant (Km).
Plasma Concentration vs time
                                                    Rectilinear Paper
                               14




                               12
Plasma Concentration (ug/mL)




                               10




                                8




                                6




                                4




                                2




                                0
                                    0   1   2   3      4      5    6    7   8   9

                                                       Time (h)
Plasma Concentration vs time
                                                      Semilog Paper
                               100
Plasma Concentration (ug/mL)




                                                                                      t½=1.2h
                                10
                                                                                      K=0.577h-1
                                                                                      V=20.833L
                                                                                      Cls=12.02L/h
                                                                                      AUC=20.797u
                                 1                                                    g/mL
                                      0   1   2   3     4      5      6   7   8   9
                                                                                      Ku=0.298h-1
                                                                                      Km=0.287h-1


                                0.1




                               0.01
                                                        Time (h)
Pharmacokinetics

Anas Bahnassi PhD RPh
                           abahnassi@gmail.com

                      http://twitter.com/abahnassi

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Pharmacokinetics: Lecture Three

  • 1. Clearance Concept Anas Bahnassi PhD RPh
  • 2. Lecture Objectives After the completion of this lecture the student should be able to: 1. Define clearance and extraction ratio and describe the relationship between them. 2. Distinguish clearance from elimination rate and elimination rate constant. 3. Explain the dependence of elimination half life on apparent volume of distribution and clearance 4. Calculate area under the plasma drug concentration versus time curve by use of the trapezoidal rule and by other methods 5. Calculate a patient’s creatinine clearance using the appropriate equation 6. Calculate dosing adjustments of a renally excreted drug in patients with various degrees of renal impairment (dysfunction).
  • 3. A Physiological Approach to Understand Clearance Concept Site of Action Heart Clearing Organ (Pump) (Kidney/Liver) The blood exiting the eliminating organ has a lower concentration than the blood entering the organ. The efficiency of Removal is quantified by the Extraction Ratio [ER].
  • 4. Extraction Ratio Extraction Ratio can be defined as the proportion of drug removed during passage through the organ. Ca Cv ������������ − ������������ ������������ = ������������
  • 5. Clearance A proportionality constant describing the relationship between a substance’s rate of elimination (amount per unit time) at a given time and its corresponding concentration Clearance in an appropriate fluid at that time. is: The hypothetical volume of blood (plasma or serum) or other biological fluids from which the drug is totally and irreversibly removed per unit time.’ Organ clearance = Blood flow rate X Extraction ratio ������������ = ������. ������������
  • 6. Hepatic Types of Clearance Clearance Renal Clearance The clearance of drug (a Metabolic fraction of total clearance) Clearance for a drug that is removed from the blood This is the total of every (plasma/serum) by individual organ clearances the process of renal that contribute to the excretion. elimination of drugs. However, the organ clearance that can be routinely determined independently in humans is renal clearance ������������������������������������������ = ������������������������������������������ + ������������������������������ ������������������������������ because this is the only organ for which we can easily determine an elimination rate.
  • 7. Clearance is a proportionality constant that relates rate of elimination (rate of excretion in renal clearance) to Plasma (or serum) concentration at any given time ������������������ ������ = ������������������ ������������ ������ ������������ ������������ ������ = ������������ ������������ ������ ������������ ������������ = ������������
  • 8. Elimination half-life vs. Clearance 0.693 ������������ = ������������ ������½ = ������ 0.693������ ������½ = ������������ Elimination half life is dependent on the volume of distribution and total clearance
  • 9. Calculating Clearance ������������������ IV Bolus ������ = ������������������ ������������ ������ ������������ Clearance for the entire dose can be obtained by integrating the right hand side of the equation from t=0 to t= ������=∞ ������������ ������������ ������������������������������ ������������������������������������������������������������������ (������������������������) ������������ ������������ ������ = = ������. ������������ ������������������������������ ������������������������ ������������������������������ ������ℎ������ ������������������������������ ������=0
  • 10. Calculating AUC IV Bolus s ������+������ ������ Area = 2 ������ ������ ������
  • 11. Calculating AUC Trapezoidal Rule: C1 or concentration1 C2 or concentration2 t1 or time1 t2 or time2 Area = ((C1 + C2)/2)(t2 – t1)
  • 12. ������=∞ Calculating AUC ������. ������������ Trapezoidal Rule: ������=������ C1 or concentration1 C2 or concentration2 t1 or time1 t2 or time2 ������=∞ ������. ������������ = Area = Sum individual trapezoids ������=������������������������ =(((C1 + C2)/2)(t2 – t1))
  • 13. ������=∞ ������. ������������ Calculating AUC ������=������ Trapezoidal Rule: C1 or concentration1 C2 or concentration2 ∞ ������������������������������������������  t1 or time1 t2 or time2 ������=∞ ������������������������ ������������������������������������������������������������������������������ ������. ������������ = ������=������������������������ ������
  • 14. Creatinine Clearance Creatinine clearance (Clcr) is renal clearance (Clr) applied to endogenous creatinine ( a product of muscles metabolism). It is used to monitor renal function and is a valuable parameter for calculating dosage regimens in elderly patients or those suffering from renal dysfunction. Normal creatinine clearance (Clcr) values are: • Adult males: 120±20mLmin-1 • Adult females: 108 ±20mLmin-1.
  • 15. Creatinine Clearance Direct measurement of Creatinine clearance Rate of ∆������������ Creatinine Excretion ∆������ ������������������������ = (������������ )������������ Creatinine Serum Concentration
  • 16. Creatinine Clearance Indirect measurement of Creatinine clearance Males: ������������������������ℎ������(������������) × (140 − ������������������ ) ������������������������ = 72 × ������������ ������������ (������������%) Females: ������������������������ℎ������(������������) × (140 − ������������������ ) ������������������������ = 0.85 72 × ������������ ������������ (������������%)
  • 17. Creatinine Clearance The significance of Creatinine clearance 1. Normal Creatinine clearance usually indicates normal kidney function 2. Creatinine clearance changes with age, physiological states, or other medical conditions and dose need to be changed accordingly 3. Dose frequency can be changed instead of changing the dos amount. 4. Changes in Creatinine clearance cause pharmacokinetic parameters to change.
  • 18. Question 1 The table shows the concentration data vs Time Cp (ug/mL) time for Cinoxacin after IV bolus (hr) administration. Plot the data and use the graph to obtain the followings: 0.25 11.6±1.3 1. Elimination half-life (t½) 0.5 8.4±1.0 2. Elimination rate constant (k) 0.75 7.2±1.1 3. Apparent volume of distribution 1 6.1±1.1 4. Systemic clearance (Cls) 1.5 4.2±1.0 5. ∞������������������ 0 2 3.2±0.9 6. Urine samples over 24 h showed the percentage of the administered dose 3 1.9±0.7 recovered unchanged was 50.1%. The rest 4 1±0.4 were metablolites. Determine the renal 6 0.3±0.2 clearance (Clr), metabolic clearance (Clm), 8 0.09±0.1 the excretion rate constant (Ku), and the metabolite rate constant (Km).
  • 19. Plasma Concentration vs time Rectilinear Paper 14 12 Plasma Concentration (ug/mL) 10 8 6 4 2 0 0 1 2 3 4 5 6 7 8 9 Time (h)
  • 20. Plasma Concentration vs time Semilog Paper 100 Plasma Concentration (ug/mL) t½=1.2h 10 K=0.577h-1 V=20.833L Cls=12.02L/h AUC=20.797u 1 g/mL 0 1 2 3 4 5 6 7 8 9 Ku=0.298h-1 Km=0.287h-1 0.1 0.01 Time (h)
  • 21. Pharmacokinetics Anas Bahnassi PhD RPh abahnassi@gmail.com http://twitter.com/abahnassi http://www.linkedin.com/in/abahnassi http://www.udemy.com/pharmacokinetics http://www.slideshare.net/abahnassi http://bahnassi.coursesites.com attribution – non-commercial – share alike