CLEARANCE

CLEARANCE :-

Ø  Clearance is the most important parameter in clinical drug applications and is useful in evaluating the mechanism by which a drug is eliminated by the whole organism or by a particular organ.

Ø  Clearance is a parameter that relates plasma drug concentration with rate of drug elimination according to following equation:

      Clearance = Rate of Elimination             -------15

                           Plasma drug concentration                                                  

Or

Cl = (dx/dt) / Cnn------16

Ø  Clearance is the theoretical volume of body fluid containing drug (i.e. that fraction of apparent volume of distribution) from which the drug is completely removed in a given period of time. It is expressed in ml/min or liters/hour.

Ø  Clearance is usually further defined as blood clearance (Cl_b), plasma clearance (Cl_p) or clearance based on unbound or free drug concentration (Cl_u) depending upon concentration C measured for the right side of equation 16.

TOTAL BODY CLEARANCE

Ø  Elimination of a drug from the body involves processes occurring in kidney, liver, lungs and other eliminating organs. Clearance at an individual organ level is called organ clearance. It can be estimated by dividing the rate of elimination by each organ with the concentration of drug presented to it. Thus,

Renal clearance      Cl_R = Rate of Elimination by kidney    ------- 17(a)                                                                                                                                               C  

Hepatic clearance    Cl_H = Rate of Elimination by liver          ------ 17(b)

                                                                C

Other organ clearance  Cl_others   = Rate of elimination by other organs   -- 17(c)

                                                                   C

Ø  Total body clearance Cl_Talso called as total systemic clearance is an additive property of individual organ clearances. Hence,

      Total systemic clearance,    Cl_T = Cl_R + Cl_H+ Cl_others------ 18

Ø  Clearance by all organs other than kidney is sometimes known as nonrenal clearance Cl_NR. It is the difference between total clearance and renal clearance.

Ø  Substituting dx/dt = K_E.X in Equation (16), we get

     

      Cl_T =     K_E.X ------ 19

                        C

Since X/C = V_d (From equation (12)), equation 19 can be written as

Cl_T= K_EV_d                                                        ------ 20

Similar Equation can be written for renal clearance and hepatic clearance

      Cl_R = K_eV_d------- 20 (a)

      Cl_H = K_mV_d------ 20 (b)

Since K_E = 0.693/t_1/2 from equation 11, clearance can be related to half life by the following equation:

Cl_T = 0.693 V_d  ------------21          

               t_½

Ø  Identical equations can be written for Cl_R and Cl_H in which cases the t_1/2   will be urinary excretion half-life for unchanged drug and metabolism half-life respectively.

Ø  From equation 21 we can conclude that, increase in t_½ results in decrease in clearance as in case with renal insufficiency and increase in V_d results in increased Cl_T as in case with obesity and other edematous condition.

Ø  The non compartmental method of computing total clearance of a drug that follows one compartment kinetics is:

      For drugs given as IV bolus,

Clt =  Xo / AUC

Ø  For drugs administered extravascularly, Clt =  FXo / AUC

     Where F is the fraction absorbed into systemic circulation.

Ø  For a drug given by IV bolus, the renal clearance Cl_R may be estimated by determining the total amount of unchanged drug excreted in urine, and AUC.

ORGAN CLEARANCE

Ø  The best way of understanding clearance is at individual organ level. Such a physiologic approach is advantageous in predicting and evaluating the influence of pathology, blood flow, enzyme activity, etc. on drug elimination. At an organ level, the rate of elimination can be written as:

Ø  Rate of Elimination by = Rate of Presentation – Rate of exit from organ    

                an organ                     to organ (input)                                                     ------ 22

Ø  Rate of Presentation (Input) = Organ blood flow x Entering concentration

                                                   =   Q. Cin------ 23

Ø  Rate of Exit (output) = Organ blood flow x Exiting concentration

                                                   = Q. Cout                                                         ----- 24

Ø  Substitution of equation 23 and 24 in equation 22 yields:

        Rate of elimination                        = Q. C _in  - Q. C_out

        (also called as rate of extraction)    = Q (C_in-C_out)                                         ------ 25

Ø  Division of above equation by concentration of drug that enters the organ of elimination

C_in yields an expression for clearance of drug by the organ under consideration.

Cl_organ = Q (C_in-C_out) =   Q. ER                                                                 ------ 26

C_in

Where ER = (C_in- C_out)/C_in which is called extraction ratio.

Ø  It has no units and its value ranges from zero (no elimination) to one (complete elimination). Based on ER values, drugs can be classified into three groups:

Ø  Drugs with high ER (above 0.7)

Ø  Drugs with intermediate ER (between 0.7 to 0.3) and

Ø  Drugs with low ER (below 0.3)

Ø  ER is an index of how efficiently the eliminating organ clears the blood flowing through it of drug.

Ø  For example, ER of 0.6 means 60% of the blood flowing through organ is completely cleared of drug.

Ø  Fraction of drug that escapes removal by organ is expressed as:

      F = 1 – ER                                                                                      ------- 27

Where F= Systemic availability when eliminating organ is liver.

RENAL CLEARANCE  

As in Equation (17.a),

 Renal Clearance Cl_R = K_e.Vd                                                                  -------- 28

                                    Or                                                                                     

CL_R=Q_R.ER_R----- 29

Where, Q_R = renal blood flow.

             ER_R = renal extraction ratio.

(Image from other sources)

Ø  In a certain disease state affecting kidney function, drugs are likely to be retained in body for longer time, this may result in accumulation of drug itself or accumulation of metabolite which may lead toxicity.

HEPATIC CLEARANCE

Ø  For certain drugs, the non renal clearance Cl_NR can be assumed as equal to hepatic clearance Cl_H. Modifying equation 18(a) gives:

Cl_H = Cl_T – Cl_R                                                                                                                                   ------ 30

Ø  An equation parallel to 26 can also be written for hepatic clearance:

Cl_H = Q_H. ER_H                                                                                                                                    ------ 31

Where Q_H = hepatic blood flow.

            ER_H = hepatic extraction ratio.

Ø  Hepatic clearance of drugs can be divided into two groups

1.      Drugs with hepatic blood flow rate limited clearance.

2.      Drugs with intrinsic – capacity limited clearance.

1.      Hepatic blood flow

Ø  When ER_H is one, Cl_H approaches its maximum value. In such a situation, hepatic clearance is said to be perfusion rate limited or flow dependent.

Ø  Alteration in hepatic blood flow significantly affects the elimination of drugs with high ER_H example propanol, lidocaine,etc.

Ø  First pass hepatic extraction is suspected when there is lack of unchanged drug in systemic circulation after oral administration.

Ø  Maximum oral availability F for such drugs can be computed from equation 27. An extension of the same equation is the non compartmental method of estimating F:

F = 1 – ER_H = AUCoral / AUCiv ------ 32

2.      Intrinsic Capacity Clearance:

Ø  It is defined as the inherent ability of an organ to irreversibly remove a drug in the absence of any flow limitation

Ø  It depends in this case upon the enzyme activity.

Ø  Drugs with  low ER_H and drugs with elimination primarily by metabolism are greatly affected by enzyme activity.

Ø  Hepatic clearance of such drugs is said to be capacity limited example theophylline. 

Hepatic clearance of drugs with low ER is independent of blood flow rate but sensitive to changes in protein binding.