Delve into the pivotal aspect of drug elimination in biopharmaceutics on our slides, offering insights into strategies and mechanisms aimed at optimizing drug disposition and refining therapeutic outcomes

1. Elimination of Drug
Guru Gobind Singh College of Pharmacy,
Yamunanagar, Haryana
Dr. Rameshwar Dass

2. Introduction
Drug elimination refers to the irreversible removal
of drug from the body by all routes of elimination.
Drug elimination is usually divided into two
major components: Excretion and Biotransformation
Excretion
• Renal Excretion
• Nonrenal Excretion of Drug

3. Renal Excretion of Drug
Drug and metabolites
• Water soluble
• Non-volatile
• Small molecular size
• Metabolised slowly
Basic functional unit of kidney
• Nephron
• Each kidney – 1 milions

4. Renal Excretion
of Drug
 Kidney

5. Renal Excretion
of Drug
 Nephron
Water Drugs
Filter Filter
80% reabsorb Secretion
10 - 20 %
reabsorbed
Reabsorption

6. Renal
Excretion of
Drug
•Principle Processes
•Glomerular Filtration
•Active tubular secretion
•Active or passive tubular
reabsorption

7. Renal
Excretion of
Drug
 Glomerular Filtration
 Non-selective and Unidirectional
 Ionised and unionised drug filtered
 Except plasma proteins/ blood cells
 Promotes retention of anionic drugs
 Driving force- hydrostatic pressure
 25 % cardiac output (1.2 l/min)
 10% filtered (120 to 130 ml/min) GFR
 GFR estimated by using creatinine, inulin,
mannitol, sodium thiosulphate

8. Renal
Excretion of
Drug
• Active tubular secretion
• Carrier mediated transport
• Energy required
• Against concentration gradient
• Two active tubular secretion methods
• Secretion of organic acids/anions
• Uric acid, Salicylic acid, penicillins,
sulphates
• Secretion of organic bases/ cations
• Endogenous amines, morphine,
• Both systems are bidirectional, non-
selective, independent of each other

9. Renal
Excretion of
Drug
• Active tubular secretion (ATS)
• It is unaffected by changes in pH and protein
binding
• It is dependent on renal blood flow
• It can be measured by using p-amino hipuric
acid
• Filtered and secreted 600 to 700 ml/min
• Proximal tubule region of nephron example:
• Probenecid + Penicillins (Decreased tubular
secretion of Penicillins)
• Probenecid + nitrofurantoin (Decreased
secretion)
• Probenecid inhibit reabsorption of uric acid

10. Renal
Excretion of
Drug
• Active or passive tubular reabsorption
• Glucose
• GFR less than 120 ml/min
• Two types
• Active process
• Passive process
• Active process
• Endogenous material
• Glucose, uric acid, electrolytes,
vitamins, amino acids

11. Renal
Excretion of
Drug
• Active or passive tubular reabsorption
• Passive process
• Exogenous materials including drugs
• Driving force concentration gradient
developed by back
• diffusion or reabsorption of water along
with electrolytes.
• Determinant: lipophilicity, polarity,
ionisation
• Factors: pH of urine, pKa of drug,
Urine flow rate

12. Renal Excretion of Drug
• Urine pH
• pH varies from 4.5 to 7.5 and depends on diet, drug intake and
pathophysiology
• Carbohydrates food- increases urinary pH
• Protein food- decreases urinary pH
• Acetazolamide, sodium bicarbonate- alkaline urine
• Excretion of drug depend on lipophilicity and pka of drug
• Very weak acids/ bases, polar drugs: reabsorption independent of urine
pH- excreated
• Weak acids (pKa > 8)/ Bases (pKa < 6), Nonpolar drugs: Unionised at
urine pH- reabsorbed.
• Strong acid/ bases: ionised all pH- excreted.
• Acidic (pKa 3-8)/ Basic (pKa 6-12): reabsorption depend on pH

13. Renal Excretion of Drug
• Urine flow
• Polar drug: Reabsorption unaffected by urine flow
• Drug with reabsorption is pH sensitive- inversely
proportional to urine flow.
• Urine flow increased by forced diuresis (mannitol).

14. Relationship between renal clearance and mechanism of clearance
* Renal Clearance ratio = Clr of drug/Clr of creatinine
Clr
ml/min
Clr Ratio
Drug to
Creatinine
Mechanism of renal clearance Example
0 0 Drug filtered & reabsorbed completely Glucose
< 130 Above 0,
below 1
Drug filtered & reabsorbed partially Lipophilic
drug
130 1 Drug filtered Creatinine
> 130 > 1 Drug filtered & secreted Polar ionic
drug
650 5 Cl = renal plasma flow rate PAH
Renal Excretion of Drug

15.  Physicochemical properties of drug
 Molecular size (300)
 pKa
 Lipid solubility
 Stereoselectivity
 Plasma concentration of drug
 I- Drug excreted by filtration
 II- Filtered + reabsorbed
 III- Filtered + secreted
Plasma Conc.
Rate
of
Excretion
III
I
II
Factors affecting renal excretion

16. Factors affecting renal excretion
Distribution and binding of drug
• Clr α 1/Vd
• If drug present in blood compartment have high excretion
• Protein bound drug not filtered- shows long half life
• Actively secreted drug have little effect of binding.
• Influence of urine pH
Blood flow to kidney
GFR and active secretion affected
Perfusion rate limited

17. Factors affecting renal excretion
• Drug interaction
• Alteration in protein binding
• Furesimide + Gentamicin (Clr increased, nephrotoxicity)
• Alteration in urine pH
• Acidification (ammonium chloride, ascorbic acid) promotes
excretion of basic drugs.
• Alkalinisation (citrates, tartarates, bicarbonates) promotes
excretion of acidicdrugs.
• Competition for active secretion (Probencid+Penicillins)
• Forced diuresis (Mannitol)

18.  Disease states
 Renal dysfunction
 Uraemia: impaired GFR
 Half-life increased
Factors affecting renal excretion
Biological factors:
Females: 10 % less than males
Newborns: 30-40% less than
normal adults
Old age: altered GFR and tubular
function

19. Renal Impairment
 Common Causes of Kidney Failure
Pyelonephritis • Inflammation and deterioration of the pyelonephrons due to
infection, antigens, or other idiopathic causes.
Hypertension
• Chronic overloading of the kidney with fluid and electrolytes may
lead to kidney insufficiency.
Diabetes mellitus
• The disturbance of sugar metabolism and acid-base balance may
lead to or predispose a patient to degenerative renal disease.
Nephrotoxic
drugs/metals
• Certain drugs taken chronically may cause irreversible kidney
damage—eg, the aminoglycosides, phenacetin, and heavy metals,
such as mercury and lead.
Hypovolemia
• Any condition that causes a reduction in renal blood flow will
• eventually lead to renal ischemia and damage.
Neophroallergens
• Certain compounds may produce an immune type of sensitivity
reaction with nephritic syndrome—eg, quartan malaria nephrotoxic
serum.

20.  Impairment of kidney function
 Affects the pharmacokinetics of drugs
 Causes of kidney failure
 Disease, injury, and drug intoxication.
 Acute diseases or trauma to the kidney
can cause uremia, (impaired filtration),
leading to accumulation of excessive
fluid and blood nitrogenous products in
the body.
 Require special dosing considerations to
pharmacokinetic and pharmacodynamic
alterations
Renal Impairment
 Kidney functions:
 Regulating body fluids,
 Electrolyte balance,
 Removal of metabolic waste,
 Drug excretion from the body

21. Renal
Function
Estimation
Estimated by measuring GFR
Markers used like Creatinine or inulin
Inulin clearance
• Tedious method
Creatinine clearance
• In body produced during muscle catabolism
• No need to collect urine
• Needs to measure serum creatinine
• Creatinine production varies with age, sex and
weight

22. Renal
Function
Creatinine clearance
• Creatinine clearance (Clcr) is renal clearance (Clr)
applied to endogenous creatinine.
• It is used to monitor renal function and calculating
dosage regimens in elderly patients or those suffering
fromrenal dysfunction.
Normal creatinine clearance (Clcr) values are:
• Adult males: 120±20mL/min.
• Adult females: 108±20mL/min.
Normal serum creatinine concentrations vary:
• Adult men: 8.0 to 13mg/L (0.8–1.3mg/dL)
• Adult women: 6.0 to 10mg/L (0.6–1.0mg/dL).

23.  Forchildren (1 to 20 years)
 Foradults (above 20 years)
 Males
 Females
70
S
0.48H W 
0.7
cr
Clcr 
cr
cr
Cl
72S

(0.48  Age)W
cr
cr
Cl
85S

(0.48  Age)W
Renal Function

24.  RF is calculated by
Serum creatinine in mg %
r
 Direct method- creatinine clearance
 Collect urine samples- 24h
Cl =
Rate of creatinine excretion
Clcr of a normal person
Clcr of patient
RF =
Renal Function

25. Renal
Function
• Renal Impairment
Based classification:
Group Description
Estimated Clcr
(mL/min)
1 Normal renal function >80 mL/min
2 Mild renal impairment 50–80 mL/min
3
Moderate renal
impairment
30–50 mL/min
4 Severe renal impairment <30 mL/min
5 ESRD Requires dialysis

26. Dose
Adjustment
in Renal
Disease

27. Dose Adjustment in Renal Disease
 Dose in patients with renal impairment can be
calculated by,
Clcr of a normal person
Clcr of patient
RF =
Drug dose in renal impairment = Normal dose x RF
 Dosing interval in patients with renal impairment can be calculated by,
Dosinginterval= Normal interval (hours)
RF

28. Extracorporeal
Removal of
drugs
Patients with end-stage renal disease and intoxicated
patients –
• Result of a drug overdose
• Require supportive treatment
• To remove the accumulated drug and its
metabolites.
Methods for the extracorporeal removal of drugs:
• Hemoperfusion
• Hemofiltration
• Dialysis
Objective: To rapidly removal of undesirable drugs
and metabolites from the body without disturbing the
fluid and electrolyte balance in the patient

29. Extracorporeal Removal of drugs
• Dialysis: Artificial process in which the accumulated drugs or waste
metabolites is removed by diffusion from the body into the dialysis fluid.
• Typesofdialysis:
• Peritoneal dialysis
• Hemodialysis (https://www.youtube.com/watch?v=EU2skU3bgS8)
• Principle to remove waste metabolites from blood or fluid by diffusion
into the dialysis fluid.
• The dialysate contains water, dextrose, electrolytes (potassium, sodium,
chloride, bicarbonate, acetate, calcium, etc), and other elements similar
to normal body fluids without the toxins.

30. Extracorporeal
Removal of
drugs
• Peritoneal Dialysis
• Membrane in the abdomen- used as the
filter.
• Visceral and parietal components.
• Large natural surface area about 1–2 m2
• Permeable to solute M.W. 30,000 Da and
70 mL/min
• Placement of catheter is surgically
simpler than hemodialysis .
• Waste metabolites discharged rapidly
into Dialysis fluid
• Fresh dialysate is reinstilled and then
drained periodically.
• Slower drug clearance rates and longer
dialysis time is required.

31. Extracorporeal
Removal of
drugs
 Continuous ambulatory peritoneal
dialysis (CAPD)
 Many diabetic patients become uremic
 About 2 L of dialysis fluid is instilled into
the peritoneal cavity via a surgically
placed catheter.
 The objective is to remove accumulated
urea and other metabolic waste
 The catheter is sealed and continue in
an ambulatory mode
 Every 4–6 hours, the fluid is emptied and
replaced with fresh dialysis fluid
 It does not require a dialysis machine and
can be performed at home.

32. Extracorporeal
Removal of
drugs
• Hemodialysis
• Uses a dialysis machine and an artificial
membrane.
• One tube inserted into an artery and
another tube inserted in a vein.
• The tubes are joined above the skin.
• Heparin is used to prevent blood clotting
during the dialysis period.
• The waste material is removed from the
blood by diffusion
• Once every 2 days to 3 times a week, for
period lasting 2 to 4 hours

33.  Hemodialysis
Physicochemical and Pharmacokinetic Properties of the Drug
Water solubility
Insoluble or fat-soluble drugs are not dialyzed. eg, glutethimide,
which is water insoluble.
Protein binding
Tightly bound drugs are not dialyzed because dialysis is a passive
process of diffusion. eg, propranolol is 94% bound.
Molecular weight
Only molecules with molecular weights of less than 500 are easily
dialyzed. eg, vancomycin is poorly dialyzed and has a molecular
weight of 1800.
Drugs with large
volumes of
distribution
Drugs widely distributed are dialyzed more slowly because the rate-
limiting factor is the volume of blood entering the machine. eg, for
digoxin, V D = 250–300 L. Drugs concentrated in the tissues are
usually difficult to remove by dialysis.
Extracorporeal Removal of drugs

34.  Hemodialysis
Characteristics of the Dialysis Machine
Blood flow rate Higher blood flows give higher clearance rates.
Dialysate Composition of the dialysate and flow rate.
Dialysis membrane Permeability characteristics and surface area.
Trans membrane pressure
Ultrafiltration increases with increase in
transmembrane pressure.
Duration and frequency of dialysis Once every 2 days to 3 times a week
Extracorporeal Removal of drugs

35. Extracorporeal
Removal of
drugs
• Hemoperfusion
• The blood through an adsorbent material and back to
the patient.
• Useful for rapid drug removal in accidental
poisoning
• The drug has great affinity for the adsorbent will be
removed.
• The two main adsorbents used
• Activated charcoal, for polar and
nonpolar drugs
• Amberlite resins are (insoluble polymeric
beads), for nonpolar organic molecules .
• Factors for drug removal by adsorbent
• Affinity to drug, surface area, absorptive capacity,
rate of blood flow, and the equilibration rate of the
drug in tissue and the blood.

36. Hemofiltration
• The process by which fluids, electrolytes, and small- molecular-weight
substances are removed from the blood by means of low-pressure flow
through hollow artificial fibers or flat-plate membranes.
• Fluid replaced to the patient for volume replacement.
• It is a slow, continuous filtration process that removes nonprotein bound,
small molecules (<10,000 Da)
• The clearance of the drug depends on the sieving coefficient and
ultrafiltration rate.
• It provides a creatinine clearance of approximately 10mL/min e.g. such as
aminoglycosides, cephalosporins, and acyclovir.
• A major problem is the formation of blood clots in filter fibers.

37. Biliary
Excretion
Hepatic cells lining the bile canaliculi produce bile.
Production and secretion is active process.
Secreted from liver & stored in gall bladder- secreted
in duodenum.
Bile flow- 0.5 to 1 ml/min
Digestion and absorption of fats.
90% absorbed back and transported to liver for secretion
and 10% excreted in faeces.
Process is capacity limited and gets saturated.
Drug clearance value 500ml/min

38. Enterohepatic Cycling
LIVER
BLOOD
SMALL
INTENSTINE
BILIARY EXCRETION
DISTRIBUTION TO TISSUES
URINARY EXCRETION
ORALADMINISTRATION
FECAL EXCRETION
HYDROLYSIS OF CONJUGATE
AND ABSORPTION
Bile
METABOLITES

39. Enterohepatic
Cycling
Advantages
• Prolongation of half lives. E.g:
carbenoxolone.
• Conservation of endogenous substances.
E.g: Vit B12 ,Vit D3
• Assessed by giving drugs parenterally-
detecting its presence in the faeces

40. Pulmonary
Excretion
Absorption at lungs by simple diffusion.
Similarly their excretion by diffusion into
expired air. e.g: general anaesthetics.
Factors influencing:
• Pulmonary blood flow
• Rate of respiration
• Solubility of the volatile substance
• Excretion of less soluble anaesthetics: high
initially declines to a lower level. same in
soluble gases too. eg: alcohol, camphor,
iodides.

41. Salivary Excretion
Passive diffusion process.
Based on pH partition hypothesis.
pH of saliva is 5.8 to 8.4.
Unionised ,lipid soluble, soluble drugs at this pH are excreted
passively

42. Salivary
Excretion
S/P ratios is < 1 for weak acids and >1 for
weak bases. basic drugs secreted more in saliva. e.g:
caffeine, theophylline etc.
Some drugs are actively excreted in saliva, e.g:
penicillin, phenytoin. etc.
Bitter taste in mouth is an indication of drug
excretion in saliva.

43. Mammary
Excretion
Important since it can gain entry into breast
feeding infant
Passive process, dependenton pH partition,
molecular weight, lipid solubility and degree
of ionisation
pH of milk varies from 6.4 - 7.6 .(mean
pH=7.0)
Weakly basicdrugs concentrate more in milk.
e.g: atropine , antihistaminics,
metronidazole.

44. Skin
Excretion
Follows pH partition hypothesis
Passive excretion of drugs
Metabolites through skin is responsible
for some hypersensitivity reactions
Example: Sulfadiazine, Sulfanilamide,
Benzoic acid

45. Bibliography
D. M. Bramhankar and S. B. Jaiswal. Biopharmaceutics
and Pharmacokinetics A Treatise. Delhi; Vallabh Prakashan. 2010​
Jambhekar SS, Breen PJ. Basic Pharmacokinetics. London;
Pharmaceutical Press. 2009.​
Shargel L, Wu-Pong S, Yu ABC. Applied biopharmaceutics and
Pharmacokinetics. McGraw Hill. 2007