Concept of clearance & factors affecting renal excretion of drug

1. PRESENTED BY
CHIRANJIBI ADHIKARIM. Pharm. 1
st
year
SUBMITTED TO
MR. KEERTHY H.S. M. Pharm.
Professor
Department of Pharmaceutics,
Mallige College of Pharmacy.
#71, SILVEPURA, BANGALORE: 560 090
EVALUATION SEMINAR ON

2. CONCEPT OF CLEARANCE
 Clearance is defined as “the hypothetical volume of body
fluids containing drug from which the drug is removed or
cleared completely in a specific period of time”.
 Clearance (Cl) = Elimination rate
Plasma drug concentration
 It is expressed in ml/min.
 Applied to all organs involved in drug elimination and
referred to as renal clearance, hepatic clearance,
pulmonary clearance, biliary clearance and so on.
 Total body clearance is the sum of individual clearances
by all eliminating organs.

3. Renal Clearance
 Renal clearance (ClR) can be defined as “the volume
of blood or plasma which is completely cleared of the
unchanged drug by the kidney per unit time”.
 ClR = Rate of urinary excretion
Plasma drug concentration
 ClR = Rate of (filtration + secretion – reabsorption)
Plasma drug concentration
 Renal clearance ratio = ClR of drug
ClR of creatinine

4. Relationship between renal clearance values and
mechanism of clearance
Renal
Clearance
(ml/min)
Renal
Clearance
Ratio
Mechanism of
Renal Clearance
Examples
0 (least value)
< 130
130 (GFR)
>130
650 (highest
value)
0
Above 0
Below 1
1
>1
5
Drug filtered and
reabsorbed
completely.
Drug filtered and
reabsorbed partially.
Drug is filtered only.
Drug is filtered and
actively secreted.
Clearance = renal
plasma flow rate.
Glucose.
Lipophilic
drugs.
Creatinine,
Insulin.
Polar, ionic
drugs.
Iodopyracet,
PAH.

5. FACTORS AFFECTING RENAL EXCRETION
OR RENAL CLEARANCE
1. Physiochemical properties of drug
2. Plasma concentration of drug
3. Distribution and binding characteristics of drug
4. Urine pH
5. Blood flow to the kidney
6. Biological factors
7. Drug interactions
8. Disease state

6. PHYSIOCHEMICAL PROPERTIES OF DRUG
 Compounds of weights < 300 Daltons, if water soluble,
easily excreted by the kidneys.
Drugs or metabolites > 500 Daltons, mainly in bile.
 Drug pKa govern the degree of ionization at the particular
pH. A polar & ionized drugs poorly reabsorbed
passively excreted rapidly.
 Ionized but lipophilic drug passively reabsorbed.
Unionized but polar excreted in urine.

7.  Stereoselective protein binding drugs drug
enantiomers exhibit differential filtration rate.
 Chloroquine, disopyramide and terbutaline
stereoselectively secreted by kidneys. ( active tubular
secretion)
 Stereoselective active tubular reabsorption
glucose and amino acids.
 Passive reabsorption is unaffected.

8. PLASMA CONCENTRATION OF DRUG
 Affects glomerular filtration and reabsorption. (passive)
 Actively reabsorbed drugs excrete in urine only when
their concentration in the glomerular filtrate > active
reabsorption capacity, e.g. glucose.

9. DISTRIBUTION AND BINDING
CHARACTERISTICS OF DRUG
 Drug with larger Vd poorly excreted in urine.
 Drugs bound to plasma protein cannot be filtered
through the glomerulus.
 ClR = Urine drug concentration × Urine flow rate
Plasma drug concentration
 F u = Cu / C
 ClR = F u × Urine flow rate

10. Drugs extensively bound to protein have longer half lives
as renal clearance is small.
Rena clearance
oxytetracycline (66% unbound) = 99 ml/min.
deoxycycline (7 % unbound) = 16 ml/min.
Actively secreted drugs are much less affected by protein
binding. E.g. penicillins.

11. BLOOD FLOW OF THE KIDNEY
 Important in case of:
Drugs excreted by glomerular filtration only.
Drugs that are actively secreted.
• In actively secreted drugs, renal clearance is perfusion
rate- limited.

12. BIOLOGICAL FACTORS
 Renal excretion is approx. 10% lower in females.
 Renal function of newborns is 30-40% less.
 In old age, the GFR is reduced and tubular function is
altered slow excretion of drugs prolonged
half-life.
 Species and strain differences, genetic make-up and
circardian rhythms also alter drug excretion.

13. DRUG INTERACTIONS
 Alteration in protein drug binding:
gentamicin induced nephrotoxicity by furosemide.
 Alteration of urine pH:
 Acidification of urine with ammonium chloride or ascorbic
acid excretion of basic drugs.
 Alkalinization of urine with citrates, tartarates and
bicarbonates excretion of acidic drugs.
 Complexation for active secretion:
phenylbutazone + hydroxyhexamide prolongs action.
Probenicid & Cimetidine are competitive inhibitors of
organic anion & cation transport system respectively.
 Forced diuretics

14. DISEASE STATES
1. Renal dysfunction greately impairs elimination of
drugs that are primarily excreted by kidneys.
2. Uraemia also impairs renal clearance of drugs.
 Increase half-lives of drugs.
 Drug accumulation.
 Toxicity.

15. Reference:
 Biopharmaceutics & Pharmacokinetics- a treatise by
DM Brahmankar and Sinil Jaiswal. 3rd edition. P.206-
211.