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Clearance concepts
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Clearance Concept
Anas Bahnassi PhD RPh
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).
Lecture Objectives
Heart
(Pump) Clearing Organ
(Kidney/Liver)
The blood exiting the eliminating organ has a lower concentration than the blood entering the organ.
A Physiological Approach to Understand Clearance Concept
The efficiency of Removal is quantified by the Extraction Ratio
[ER].
Site of
Action
Ca
Cv
Extraction Ratio Extraction Ratio can be defined
as the proportion of drug removed during passage through the organ.
𝑬𝑹 =𝑪𝒂 − 𝑪𝒗𝑪𝒂
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 in an appropriate fluid at that time.
Clearance
The hypothetical volume of blood (plasma or serum) or other
biological fluids from which the drug is totally and irreversibly
removed per unit time.’
Clearance is:
Organ clearance = Blood flow rate X Extraction ratio
𝑪𝒍 = 𝑸. 𝑬𝑹
Types of Clearance
This is the total of every individual organ clearances
that contribute to the 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.
The clearance of drug (a fraction of total clearance) for a drug that is removed
from the blood (plasma/serum) by the process of renal
excretion.
Renal Clearance
Metabolic Clearance
Hepatic Clearance
𝑪𝒍𝑻𝒐𝒕𝒂𝒍 = 𝑪𝒍𝑹𝒆𝒏𝒂𝒍 + 𝑪𝒍𝑵𝒐𝒏 𝑹𝒆𝒏𝒂𝒍
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
𝑑𝑥𝑢𝑑𝑡
𝑡= 𝐶𝑙𝑟 𝐶𝑝 𝑡
𝑑𝑥
𝑑𝑡 𝑡= 𝐶𝑙 𝐶𝑝 𝑡
𝐶𝑙 = 𝑘𝑉
𝐶𝑙 = 𝑘𝑉 𝑡½ =0.693
𝑘
𝑡½ =0.693𝑉
𝐶𝑙
Elimination half life is dependent on the volume of distribution and total clearance
Elimination half-life vs. 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=
Calculating Clearance
𝑑𝑥𝑢𝑑𝑡
𝑡= 𝐶𝑙𝑟 𝐶𝑝 𝑡
𝐶𝑙𝑇 =
𝑑𝑥𝑑𝑡
𝑑𝑡
𝐶. 𝑑𝑡
𝑡=∞
𝑡=0
=𝑇𝑜𝑡𝑎𝑙 𝐸𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑖𝑒𝑑 (𝐷𝑜𝑠𝑒)
𝑇𝑜𝑡𝑎𝑙 𝐴𝑟𝑒𝑎 𝑢𝑛𝑑𝑒𝑟 𝑡ℎ𝑒 𝑐𝑢𝑟𝑣𝑒
s IV Bolus
Area =𝑎+𝑏 𝑐
2
𝑎 𝑏
𝑐
Calculating AUC
Trapezoidal Rule:
C1 or concentration1
C2 or concentration2
t1 or time1
t2 or time2
Area = ((C1 + C2)/2)(t2 – t1)
Calculating AUC
C1 or concentration1
C2 or concentration2
t1 or time1 t2 or time2
= Area = Sum individual trapezoids
=(((C1 + C2)/2)(t2 – t1))
Trapezoidal Rule:
𝑪.𝒅𝒕
𝒕=∞
𝒕=𝒍𝒂𝒔𝒕
𝑪.𝒅𝒕
𝒕=∞
𝒕=𝟎
Calculating AUC
C1 or concentration1
C2 or concentration2
t1 or time1 t2 or time2
=𝑳𝒂𝒔𝒕 𝑪𝒐𝒏𝒄𝒆𝒏𝒕𝒓𝒂𝒕𝒊𝒐𝒏
𝒌
Trapezoidal Rule:
Calculating AUC
𝑪.𝒅𝒕
𝒕=∞
𝒕=𝒍𝒂𝒔𝒕
𝑪. 𝒅𝒕
𝒕=∞
𝒕=𝟎
𝑨𝑼𝑪𝑳𝒂𝒔𝒕∞
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
𝐶𝑙𝐶𝑟 =
∆𝑥𝑢∆𝑡
(𝐶𝑠)𝐶𝑟
Direct measurement of Creatinine clearance
Rate of Creatinine Excretion
Creatinine Serum Concentration
Creatinine Clearance
𝐶𝑙𝐶𝑟 =𝑊𝑒𝑖𝑔ℎ𝑡(𝑘𝑔) × (140 − 𝑎𝑔𝑒 )
72 × 𝐶𝑠 𝐶𝑟(𝑚𝑔%)
Indirect measurement of Creatinine clearance
𝐶𝑙𝐶𝑟 = 0.85𝑊𝑒𝑖𝑔ℎ𝑡(𝑘𝑔) × (140 − 𝑎𝑔𝑒 )
72 × 𝐶𝑠 𝐶𝑟(𝑚𝑔%)
Males:
Females:
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 for Cinoxacin after IV bolus administration. Plot the data and use the graph to obtain the followings: 1. Elimination half-life (t½) 2. Elimination rate constant (k) 3. Apparent volume of distribution 4. Systemic clearance (Cls) 5. 𝐴𝑈𝐶0
∞ 6. Urine samples over 24 h showed the
percentage of the administered dose recovered unchanged was 50.1%. The rest were metablolites. Determine the renal clearance (Clr), metabolic clearance (Clm), the excretion rate constant (Ku), and the metabolite rate constant (Km).
Time (hr)
Cp (ug/mL)
0.25 11.6±1.3
0.5 8.4±1.0
0.75 7.2±1.1
1 6.1±1.1
1.5 4.2±1.0
2 3.2±0.9
3 1.9±0.7
4 1±0.4
6 0.3±0.2
8 0.09±0.1
0
2
4
6
8
10
12
14
0 1 2 3 4 5 6 7 8 9
Pla
sma
Co
nce
ntr
atio
n (
ug
/mL)
Time (h)
Plasma Concentration vs time Rectilinear Paper
0.01
0.1
1
10
100
0 1 2 3 4 5 6 7 8 9
Pla
sma
Co
nce
ntr
atio
n (
ug
/mL)
Time (h)
Plasma Concentration vs time Semilog Paper
t½=1.2h K=0.577h-1
V=20.833L Cls=12.02L/h AUC=20.797ug/mL Ku=0.298h-1
Km=0.287h-1
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Anas Bahnassi PhD RPh
Pharmacokinetics
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