DEPARTMENT . OF PHARMACEUTICS. . CONTENTS. . Renal clearance. . Hepatic clearance. . Organ clearance. . Total clearance. . Gut wall clearance . . Lung clearance. ID: 681132
DownloadNote - The PPT/PDF document "CONCEPT OF CLEARANCE" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
CONCEPT OF CLEARANCE
DEPARTMENT OF PHARMACEUTICSSlide2
Gut wall clearance
“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.
plasma drug concentrationSlide4
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
= 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 concentrationSlide5
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
which is cleared by
glomerular filtration only. The ratios of these 2 values is called as “Renal clearance ratio or Excretion ratio”
R of drugRenal
R of creatinineSlide6
FACTORS AFFECTING RENAL CLEARANCE
Physicochemical properties of drug
Plasma concentration of drug
Blood flow to the kidneys
Distribution and binding characteristics of the drug
Drug interactionsDisease statusBiological factorsSlide7
PHYSICO CHEMICAL PROPERTIES
PH,pKa and lipid solubilityComponuds which are having small molecular weight can be filtered easily through Glomerulus. 300-500 daltons(urine and bile) > 500
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
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
(polar) one will be excreted .Slide8
For example :
Very weakly acidic non-polar drugs (
pKa>8) like phenytoin or very weakly basic non-polar Drug (
are mostly unionised through iout the entire range of Urine Ph,and are extensively reabsorbed passively at all urine
excretionOf such drug is always low.A strongly acidic drug (
pKa≤ 2) like
acid or a strongly basic drug(pKa≥ 12) Like guanithidine
at all pH
its rate of excretion is always High.
Acidic Drugs like
or basic drugs like
are polar in its
form Is not reabsorbed passively irrespective of extent of
of such drug is Independent of PH of urine.Slide9
PLASMA CONCENTRATION OF THE DRUG
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 concentrationsSlide10
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
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
R =fu X urine flow rateSlide11
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 FACTORSSlide12
Any drug interaction that results in alteration of protein-drug binding characteristics, renal flood flow, active secretion, urine pH and intrinsic clearance and forced
would alter renal clearance of a drug. Alteration in P-D binding
: An interesting example of this is
nephrotoxicity by furosemide.Alteration of Urine pH
: Acidification of urine with ammonium chloride,
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
, for active secretion and thus prolongs its action.
: All diuretics increase elimination of drugs whose renal clearance gets affected by urine flow rate.
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.
, 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 IMPAIRMENTSSlide14
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).Slide15
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
by the organ is expressed as:
F = 1 – ER.
when the eliminating organ is liver.Slide16
TOTAL BODY CLEARANCE
is an additive property of individual organ clearances.
Total Systemic Clearance= ClT
R + ClH
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
= (dx/dt) KE.X = =
= 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.Slide17
i.v, bolus the total clearance is X0 ClT = AUC
FX0 ClT =
For a drug given by
. bolus, the renal clearance ClR may be estimated by determining the total amount of unchanged drug excreted in urine, Xu ∞ and AUC. Xu ∞ ClT = t1/2Slide18
For certain drugs, the
nonrenal clearance can be assumed as equal to hepatic clearance Cl
It is given as:
ClH = CLT -
= Hepatic blood flow (about 1.5
= 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.
approaches its maximum value i.e. hepatic blood flow. In such a situation, hepatic clearance is said to be
Alteration in hepatic blood flow significantly affects the elimination of drugs with high ERH e.g.
, lidocaine, etc. Such drugs are removed from the blood as rapidly as they are presented to the liver (high first-pass hepatic metabolism).Slide19
REFERENCESText book of
biopharmaceutics and pharmacokinetics by v.venkateswarulu, page no135-160.2. Text book of
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
Ppts downloaded from www.google.comSlide20