CONCEPT OF CLEARANCE

CONCEPT OF CLEARANCE

DEPARTMENT OF PHARMACEUTICS

CONTENTS

Renal clearance

Hepatic clearance

Organ clearance

Total clearance

Gut wall clearance

Lung clearance

DEFINITION:

“Clearance is defined as the hypothetical volume of body fluids containing drug from which the drug is removed

or cleared completely in a specified period of time.”

it is expressed in ml/minute.

elimination rate

Clearance =

plasma drug concentration

RENAL CLEARANCE

DEFINITION :

it can be defined as the volume of blood or plasma which is completely cleared of the unchanged drug by the kidney per unit time.it is expressed as follows

Rate of urinary excretion

CL

R

= plasma drug concentrationSimply we can say, Renal clearance is the ratio of “ sum of rate of glomerular filtration and active secretion minus rate of reabsorption” to “plasma drug concentration (C)”

rate of filtration + rate of secretion - rate of

reabsorption.CLR = plasma drug concentration

Renal clearance cannot be determined

directly,but how ever

It is determined by comparing the clearanc evalues

obtained for the drug with that of an agent like

creatinine,insulin

which is cleared by

glomerular filtration only. The ratios of these 2 values is called as “Renal clearance ratio or Excretion ratio”

CL

R of drugRenal

clearanceratio =

CL

R of creatinine

FACTORS AFFECTING RENAL CLEARANCE

Physicochemical properties of drug

Plasma concentration of drug

Urine pH

Blood flow to the kidneys

Distribution and binding characteristics of the drug

Drug interactionsDisease statusBiological factors

PHYSICO CHEMICAL PROPERTIES

Molecular size,

PH,pKa and lipid solubilityComponuds which are having small molecular weight can be filtered easily through Glomerulus. 300-500 daltons(urine and bile) > 500

daltons

(less extent)

Urinary excretion of an

unchange drug is inversely related to its lipophilicity. because lipophilic drug is passively reabsorbed to a large extent.pHThe pH of urine depends the diet,drug intake and the pathophysiology of the patient.food rich in carbohydrates results in high urinary PH where as protiens lowers it.

Renal clearance(ml/min) = U/P

Χ

urine flow rate(ml/min)PKaRenal clearance is PH dependent procedure. PH dependent excretion greatly depends upon its pKa & lipid solubility.at particular PH, pKa depends upon degree of ionisation.Polar and ionised

drug will be passively reabsorbed and excreted rapidly.Ionised (lipophilic drug) will be reabsorbed .where as

unionised

(polar) one will be excreted .

For example :

Very weakly acidic non-polar drugs (

pKa>8) like phenytoin or very weakly basic non-polar Drug (

pKa

<6) like

propoxyphene

are mostly unionised through iout the entire range of Urine Ph,and are extensively reabsorbed passively at all urine

pH.The

rate of

excretionOf such drug is always low.A strongly acidic drug (

pKa≤ 2) like

cromoglycic

acid or a strongly basic drug(pKa≥ 12) Like guanithidine

is completely

ionised

at all pH

valuesand

its rate of excretion is always High.

Acidic Drugs like

pencillin

or basic drugs like

gentamicin

are polar in its

unionised

form Is not reabsorbed passively irrespective of extent of

ionisation.excretion

of such drug is Independent of PH of urine.

PLASMA CONCENTRATION OF THE DRUG

Glmerular

filtration and rebsorption are directly affected by plasma drug concentration Since both are passive processes. A drug that is not bound to plasma proteins are Excreted by filtration only,

1. Shows a linear Relationship between rate of excretion and plasma concentration

2. In case of drugs secreted or reabsorbed actively the rate process increases with an increase in plasma concentration to a point when saturation of carriers occur.

In case of actively

rabsorbd drugs excretion is negligible at low plasma concentrations

DISTRIBUTION AND BINDING CHARACTERISTICS OF THE DRUG

Clearance is inversely related to the apparent volume of distribution of drugs.

As the Vd increases rat of clearance decreases.Drugs that are bound to plasma proteinsBehaves as macro molecules and thus cannot be filtered through the glomerulus. Only unbound or free drug appear in the

glomerular

filtrate.

urine concentration

CLR = x urine flow rate plasma concentrationSince only free drug can b excreted in the urine,the fraction of drug bound to plasma proteins is important. And it can be computed as fu=cu/cWhere, fu is the fraction of drug unbound to the plasma, cu is the concentration of unbound drug in the plasma, C is total plasma concentration of the drug.Therefore the equatio

is rewritten as

CL

R =fu X urine flow rate

Blood Flow to the Kidneys

The renal blood flow is important in case of drugs excreted by glomerular filtration only and those that are actively secreted. In the latter case, increased perfusion increases the contact of drug with the secretory

sites and enhances their elimination. Renal clearance in such instances is said to be perfusion rate-limited.Biological Factors Age, sex, species and strain differences, differences in the genetic make-up, circadian rhythm, etc. alter drug excretion. Renal excretion is approximately 10% lower in females than in males. The renal function of newborns is 30 to 40% less in comparison to adults. In old age, the GFR is reduced and tubular function is altered.

BLOOD FLOW TO THE KIDNEYS AND BIOLOGICAL FACTORS

Any drug interaction that results in alteration of protein-drug binding characteristics, renal flood flow, active secretion, urine pH and intrinsic clearance and forced

diuresis

would alter renal clearance of a drug. Alteration in P-D binding

: An interesting example of this is

gentamicin

induced

nephrotoxicity by furosemide.Alteration of Urine pH

: Acidification of urine with ammonium chloride,

methionine

or ascorbic acid enhances excretion of basic drugs. Alkalinisation of urine with citrates, tartarates, bicarbonates and carbonic anhydrase

inhibitors promote excretion of acidic drugs.

Competition for Active Secretion

: Phenylbutazone competes with hydroxyhexamide

, the active metabolite of

antidiabetic

agent

acetohexamide

, for active secretion and thus prolongs its action.

Forced

Diuresis

: All diuretics increase elimination of drugs whose renal clearance gets affected by urine flow rate.

DRUG INTERACTIONS

RENAL DYSFUNCTION

Some of the causes of renal failure are hypertension, diabetes mellitus, hypovolemia (decreased blood supply to the kidneys), pyelonephritis (inflammation of kidney due to infections, etc.), nephroallergens

(e.g. nephrotoxic serum) and nephrotoxic agents such as aminoglycosides, phenacetin and heavy metals such as lead and mercury.

URAEMIA

, characterized by impaired glomerular filtration and accumulation of fluids and protein metabolites, also impairs renal clearance of drugs. In both these conditions, the half-lives of drugs are increased. As a consequence, drug accumulation and toxicity may result.  DISEASE –STATES AND RENAL IMPAIRMENTS

ORGAN CLEARANCE

At an organ level, the rate of elimination can be written as:

Rate of elimination

by an organ = Rate of presentation - Rate of exit from the organ

to the organ

Rate of presentation (input) = Organ blood flow X Entering concentration 

  = QCinRate of exit (output ) = Organ blood flow X Exiting concentration = QC out of Rate of elimination = rate of input –rate of output =(QCin-QCout) = (QCin-Cout

)

Rate of extraction =

Clorgan = QCin-Qcout Cin Cinwhere, ER = (Cin – Cout)/

Cin is called as extraction ratio. 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 3 groups:

1. Drugs with high ER (above 0.7), 2. Drugs with intermediate ER (between 0.7 to 0.3), 3. Drugs with low ER (below 0.3).

ER

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

.

For example, an ER of 0.6 tells that 60% of the blood flowing through the organ will be completely cleared of drug.

The fraction of drug that

escapes removal

by the organ is expressed as:

F = 1 – ER.

where,

F

=

systemic availability

when the eliminating organ is liver.

TOTAL BODY CLEARANCE

is an additive property of individual organ clearances.

Total Systemic Clearance= ClT

=

Cl

R + ClH

+

Cl

others 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. CL

T

= (dx/dt) KE.X = =

K

E

.Vd

[X/C=

Vd

]

C

C

Cl

R

=

Ke.Vd

,

Cl

H

=

Km.Vd

0.693

Vd

CL

T

= t1/2ClR and ClH in which cases the t½ will be urinary excretion half-life for unchanged drug and metabolism half-life respectively.shows that as ClT decreases, as in renal insufficiency, t½ of the drug increases. As the ClT takes into account Vd, changes in Vd as in obesity or oedematous condition will reflect changes in ClT.

For

i.v, bolus the total clearance is X0 ClT = AUC

FX0 ClT =

AUC

For a drug given by

i.v

. bolus, the renal clearance ClR may be estimated by determining the total amount of unchanged drug excreted in urine, Xu ∞ and AUC. Xu ∞ ClT = t1/2

HEPATIC CLEARANCE

For certain drugs, the

nonrenal clearance can be assumed as equal to hepatic clearance Cl

H

.

It is given as:

ClH = CLT -

Cl

R

ClH

=

QH. ER

H

where, Q

H

= Hepatic blood flow (about 1.5

liters

/min), and

ER

H

= Hepatic extraction ratio.

The hepatic clearance of drugs can be divided into two groups:

1. Drugs with hepatic blood flow rate-limited clearance, and

2 . Drugs with intrinsic capacity-limited clearance.

HEPATIC CLEARANCE:

When ER

H

is one,

Cl

H

approaches its maximum value i.e. hepatic blood flow. In such a situation, hepatic clearance is said to be

perfusion rate-limited

or

flow-dependent

.

Alteration in hepatic blood flow significantly affects the elimination of drugs with high ERH e.g.

propranolol

, lidocaine, etc. Such drugs are removed from the blood as rapidly as they are presented to the liver (high first-pass hepatic metabolism).

REFERENCESText book of

biopharmaceutics and pharmacokinetics by v.venkateswarulu, page no135-160.2. Text book of

biopharmaceutics

and pharmacokinetics a

treatise, page no139-193.

Bio-pharmacokinetics&clinical pharmacokinetics by milo gibaldi,3rd edition,pageno187-193 Encyclopedia of pharmaceutical technology by james swarbrick,3rd

edition,volume-3.

5.

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