RENAL DRUG ELIMINATION

PRESENTED BY-MUHAMMAD SHOAIB ALI, QASIM NAZEER AND WAQAS ALI

DRUG ELIMINATION-• It is the irreversible removal of the drug from the body by

all routes of elimination.

• Usually divided into two components :

i. Excretion

ii. Biotransformation

• Drug elimination in the body involves many complex rate processes,

• Elimination processes may vary in each organ which is eliminating drug.

DRUG EXCRETION-• It is the removal of the intact drug.

• Drugs are mainly excreted by renal excretion.

• Other pathways : Excretion of drug in to bile, sweat, milk ( via lactation ), lungs, or other body fluids.

CLEARANCE-• It is the process of drug elimination from the body

or from a single organ without identifying the individual processes involved.

• It may also be defined as ;

“ the volume of fluid cleared of drug from the body per unit of time.”

• Units : mL/min or L/hr or unit/min

THE KIDNEY:• ANATOMY-

THE KIDNEY:• PHYSIOLOGY:

– One of the major eliminating organ of the body, and so as for the drugs.

– Two major endocrine functions it performs;

• Secretion of renin

• Secretion of erythropoietin

THE KIDNEY:

THE KIDNEY:• BLOOD SUPPLY:

– The kidneys represent about 0.5% of the total body weight and receive approximately 20–25% of the cardiac output.

• Renal Blood Flow:

– renal blood flow (RBF) is the volume of blood flowing through the renal vasculature per unit time. Renal blood flow exceeds 1.2 L/min or 1700 L/day.

• Renal Plasma Flow:

– Renal plasma flow (RPF) is the renal blood flow minus the volume of red blood cells present.

THE KIDNEY:• RELATIONSHIP BETWEEN RPF AND RBF:

• Assuming a hematocrit of 0.45 and a RBF of 1.2 L/min, using the above equation,

RPF = 1.2 – (1.2 x 0.45) = 0.66 L/min or 660 mL/min

– approximately 950 L/day.

THE KIDNEY:• GLOMERULAR FILTRATION RATE:

– “The volume of water filtered out of the plasma through glomerular capillary walls into Bowman's capsules per unit of time.”

• Normal value:

– The glomerular filtration rate (GFR) is about 125 mL/min in an average adult, or about 20% of the RPF.

• The ratio GFR/RPF is the filtration fraction.

THE KIDNEY:• REGULATION OF RENAL BLOOD FLOW:

• Basic determinants –

– Renal arterial pressure

– Glomerular capillary hydrostatic pressure

THE KIDNEY:• GLOMERUAL FILTRATION AND URINE FORMATION:

• A normal adult male subject has a GFR of approximately 125 mL/min.

• About 180 L of fluid per day are filtered through the kidneys.

• In spite of this large filtration volume, the average urine volume is 1–1.5 L.

THE KIDNEY:

DRUG ELIMINATION-• Elimination can occur by one or more pathways.• Rate of overall elimination process is governed by

elimination rate constant ‘k’.• If a drug is excreted by renal excretion, metabolism

and biliary excretion, overall elimination rate constant k will be equal to,

– k = ke + km + kb

• Multiplying both the sides by Vd,– kVd = keVd + kmVd + kbVd OR

– Total Body Clearance = Renal Clearance + Metabolic clearance + Biliary clearance

RENAL DRUG EXCRETION-• It is major route of elimination for many drugs.

• Three major processes : 1. Glomerular Filtration

2. Active Tubular Secretion

3. Tubular Reabsorption

MECHANISM OF DRUG EXCRETION-• GLOMERULAR FILTRATION:– Uni-directional process for molecules less than weight of

500.

– Molecules include un-dissociated (non-ionized) and dissociated (ionized).

– Protein-bound drugs do not get filtered.

– Major driving force is the hydrostatic pressure.

GLOMERULAR FILTRATION-• GFR is measured by using a drug that is eliminated

by filtration only (i.e., the drug is neither reabsorbed nor secreted).

• Examples:• Inulin

• Creatinine

• So, clearance of inulin would be equal to the normal GFR i.e. 125-130 mL/min.

• GFR is directly proportional to concentration of free drug in plasma.

ACTIVE TUBULAR SECRETION-• It is an active transport process, meaning requires energy.

• This system is capacity limited and may be saturated.

• Two active systems have been identified, systems for;– Weak acids

• e.g, Probenecid and Penicillins

– Weak bases

• e.g, Ondansetron hydrochloride

• Drugs commonly used to measure active tubular secretion include p-amino-hippuric acid (PAH) and iodopyracet (Diodrast).

ACTIVE TUBULAR SECRETION-• The elimination half life of drugs, actively secreted

by the kidney, is small.

• Example: • Penicillins are extensively protein bound, but their elimination

half-lives are short due to rapid elimination by active secretion.

TUBULAR REABSORPTION-• Tubular reabsorption occurs after the drug is

filtered through the glomerulus and can be an active or a passive process.

• Drug may be completely reabsorbed, e.g. Glucose; clearance value for such component would be zero.

• If partially reabsorbed, then value is always less than normal GFR i.e., 125–130 mL/min.

TUBULAR REABSORPTION-• It is influenced by the pH of the urine and the pka value of

the drug.

• These factors render the drug to be in dissociated or un-dissociated form.

• Un-dissociated drugs are easily reabsorbed.

• Normal urinary pH may vary from 4.5 to 8.0.

• Drugs can decrease (acidify) e.g.,ascorbic acid or increase ( alkalanize ) e.g., Sodium carbonate the pH of the urine.

• Most important changes in urinary pH are caused by fluids administered intravenously– e.g. Solutions of bicarbonate or ammonium chloride.

TUBULAR REABSORPTION

TUBULAR REABSORPTION-• The percentage of ionized weak acid and basic drug

can be obtained from the Henderson–Hesselbalch equation.

• For acidic :

• For basic :

RENAL EXCRETION RATE

DETERMINATION OF RENAL EXCRETION RATE• As renal excretion rate of most drugs follows first-

order kinetics, the renal excretion rate at any time is equal to;

• Where,– Ae is the amount of the drug excreted in urine

– ke is the first-order renal excretion rate constant

– A is the amount of the drug in the body.

DETERMINATION OF RENAL EXCRETION RATE• But as urine samples are usually collected over

certain time intervals, so;

• Where,– ΔAe is the amount of the drug excreted in urine over a

certain urine collection interval Δt

– ΔAe/Δt is the renal excretion rate

– ke is the first-order renal excretion rate constant

– Aaverage is the average amount of the drug in the body during the urine collection interval

EXPERIMENTAL DETERMINATION OF RENAL EXCRETION RATE• Select the length of time for each of the urine collection intervals

• Collect urine samples at the end of each urine collection interval

• Measure the volume of each urine sample

• Determine the drug concentration in each urine sample

• Calculate the amount of the drug excreted during each urine collection interval as;– Amount excreted = Drug conc. in urine X Sample volume

• Calculate the renal excretion rate as,– Renal excretion rate = Amount excreted / Time of urine collection

RENAL EXCRETION RATE-TIME PROFILE• Renal excretion rate after a single IV dose can be

described by

• Where,– ke is the renal excretion rate constant

– Ao is the initial amount of the drug in the body

– k is the overall elimination rate constant

RENAL EXCRETION RATE-TIME PROFILE• Plotting the renal excretion rate versus time on semilog graph paper will

give us a straight line, and also we can calculate half-life and renal excretion rate constant of the drug.

RENAL CLEARANCE• It defined as,

“ the volume of the blood or plasma that is completely cleared of the drug per unit time by the kidney”

• Renal excretion rate is determined by,

• Where,–At-mid is the amount of the drug in the body at the midpoint of the urine collection interval i.e., approximately equal to the average amount of the drug during the urine collection interval.

RENAL CLEARANCE• Now, as the amount of drug is equal to the drug

concentration times the volume of distribution, so the previous equation becomes,

– Cpt-mid is the drug plasma conc. at the midpoint of the urine collection interval

• And,

– Because ke X Vd = Renal clearance

RENAL CLEARNCE• Plotting renal excretion rate versus the plasma

conc. at the middle of the urine collection interval would give a straight line on the graph paper, and slope of the line is equal to the renal clearance.

RENAL CLEARANCE• Interpretation of renal clearance of drugs in

comparison with GFR-– Drugs with renal clearance larger than the GFR are

actively secreted in the renal tubules.

– Drugs with renal clearance lower than the GFR are most probably filtered and then reabsorbed OR drugs undergo filtration, tubular secretion and then are reabsorbed.

CREATININE CLEARANCE AS A MEASURE OF KIDNEY FUNTION• Renal clearance of creatinine represents an accurate

measure of the GFR. It is determined as,– Collect all the urine excreted over a period of 24 hr

– Obtain plasma sample and determine plasma creatinine concentration

– Determine the total volume of the urine collected and the creatinine concentration in the urine sample

– Calculate the total amount of creatinine excreted by,

• Amount = Volume of urine X Concentration of creatinine

– Calculate the creatinine excretion rate by,

• Creatinine excretion rate = Amount excreted / Time of urine collection

– Calculate the creatinine clearance by,

• Creatinine clearance= Creatinine excretion rate/Creatinine plasma conc.

DETERMINATION OF CREATININE CLEARANCE• Example-– Patient is asked to collect urine over a 24h hr period

– Total volume of urine collected = 2200mL

– Creatinine conc. in urine was found to be 0.2 mg/mL

– Creatinine conc. in the serum was 3.0 mg/100mL• We want to calculate the creatinine clearance of this patient.

Cont’d…

DETERMINATION OF CREATININE CLEARANCE• Total amount of creatinine excreted in 24 hrs,

– Urine volume X Urine concentration

– 2200 mL X 0.2 mg/mL = 440 mg

• Creatinine excretion rate is calculated as follows,– 440 mg / 24 hr x 60 min/hr = 0.3055 mg/min

• So creatinine clearance would be,– Creatinine excretion rate /Serum creatinine concentration i.e.,

– 0.3055 mg/min / 3 mg/100 mL

– = 10.2 mL/min

APPLICATIONS OF RENAL DRUG ELIMINATION• Estimation of GFR

• Estimation of renal plasma flow

• Measurement of filtration fraction

• Estimation of kidney function

DETERMINATION OF PHARMACOKINETIC PARAMETERS FROM RENAL EXCRETION RATE DATA • Elimination rate constant and half-life (k and t1/2)

• Renal excretion rate constant ke

• Volume of distribution Vd

• Renal clearance CLR

• Fraction of dose excreted unchanged in urine

• Bioavailability

THANKYOU FOR YOUR ATTENTION