Lecture ObjectivesAfter the completion of this lecture the studentshould 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 clearance4. Calculate area under the plasma drug concentration versus time curve by use of the trapezoidal rule and by other methods5. Calculate a patient’s creatinine clearance using the appropriate equation6. Calculate dosing adjustments of a renally excreted drug in patients with various degrees of renal impairment (dysfunction).
A Physiological Approach toUnderstand ClearanceConcept 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 definedas the proportion of drug removedduring 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 concentrationClearance 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 routinelydetermined 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 thevolume 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 Trapezoidal Rule: C1 or concentration1 C2 or concentration2t1 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 ClearanceCreatinine clearance (Clcr) is renal clearance (Clr) appliedto endogenous creatinine ( a product of musclesmetabolism). It is used to monitor renal function and is avaluable parameter for calculating dosage regimens inelderly patients or those suffering from renal dysfunction.Normal creatinine clearance (Clcr) values are:• Adult males: 120±20mLmin-1• Adult females: 108 ±20mLmin-1.
Creatinine ClearanceDirect measurement of Creatinine clearance Rate of ∆ Creatinine Excretion ∆ = ( ) Creatinine Serum Concentration
Creatinine Clearance The significance of Creatinine clearance1. Normal Creatinine clearance usually indicates normal kidney function2. Creatinine clearance changes with age, physiological states, or other medical conditions and dose need to be changed accordingly3. 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 vsTime 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 distribution1 6.1±1.1 4. Systemic clearance (Cls)1.5 4.2±1.0 5. ∞ 02 3.2±0.9 6. Urine samples over 24 h showed the percentage of the administered dose3 1.9±0.7 recovered unchanged was 50.1%. The rest4 1±0.4 were metablolites. Determine the renal6 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 12Plasma 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 100Plasma 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)