Drug Excretion

Lecture Plan
1. Concept of drug elimination

2. Routes of Elimination
3. Drug elimination in disease states Renal disease, hepatic disease 4. Quantification of rate of elimination
Concept of clearance

5. Drug elimination in special population Children, elderly

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1. Concept of Drug Excretion

2. Routes of Elimination
RENAL EXCRETION

HEPATIC and gastrointestinal excretion (feces)

PULMONARY EXCRETION OTHER ROUTES Hair Tears Sweat

Dialysis (hemodialysis)
Breast milk
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RENAL EXCRETION

KIDNEY FUNCTION
MEASUREMENT OF KIDNEY FUNCTION
GFR (glomerular filtration rate) is considered the best

index of kidney function.

Normal GFR in young adults it is approximately 120 -

130ml/min/1.73 m2 (<< normal body area)

A decrease precedes the onset of kidney failure. A persistently reduced GFR is a specific indication of

chronic kidney disease (CKD).

Below 60 mL/min/1.73 m2 prevalence of complications

of CKD increases.
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2.1. RENAL EXCRETION OF DRUGS

Introduction The major organ for the excretion of drugs is the kidney. rate of renal elimination vary from 1% (chlorpropamide) to 99 % (penicillin) The nephron is the functional unit of the kidney. Each consists of a renal corpuscle (made up of Bowman's capsule and a glomerulus) and a renal tubule. The renal tubule consists of the convoluted tubule and the Loop of Henle.
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RENAL EXCRETION of drugs

Mechanisms of Renal disposition of drugs Glomerular filtration active tubular secretion tubular re-absorption Biotransformation

Kidney
Glomerular Filtration Rate (GFR) 125ml/min

Urine 1ml/min

Plasma flow 650ml/min Filtration

Acid Base

99% of H20 + Lipid soluble drugs Re-absorption

Active secretion

Nov 6, 2007

Determinants of ADME

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Active Secretion
Detected when the overall rate of

urinary drug excretion exceeds the rate of filtration Secretory processes (proteins) located predominantly within the proximal tubules Mechanisms exist for secreting acids (anions) and bases (cations) from plasma into the tubular lumen Energy-dependent Saturable processes Subject to competitive inhibition Effect of Protein-Binding Depends upon secretion efficiency and contact time at the secretory sites Restrictive (dependent on the Fub) vs. Non-Restrictive (perfusion-rate limited)

RENAL EXCRETION :Glomerular Filtration

Kidney receives 1.1 L of blood (20 25%) of

cardiac output About 10% of the blood which enters the glomerulus is filtered Compounds with Mol.wt < 20,000 filtered More than 90% of the filtrate is reabsorbed (normal urinary volume is about 1 2 L/day). GFR = 120 ml/min CLR of Inulin - a measure of GFR
Filtered freely into the tubule Not influenced by protein binding and neither secreted nor reabsorbed

Rate of filtration = Fu. Cp.GFR Not a very effective drug extraction process

(maximal ~ 0.11 or 10 %)

RENAL EXCRETION: Tubular Secretion

In the proximal tubule there is active secretion of

some weak electrolyte, especially weak acids. It requires a carrier and a supply of energy and may be subject to competitive inhibition.
Tubular secretion constitute 80% renal plasma Carriers (competitive)
acid pump: transport acidic drugs (aspirin, penicillin, probenicid, phenylbutazone, sulfathiazole, frusemide, thiazides) and endogenous substance (uric acid) base pump: transport basic drugs (histamine, dopamine, procaine, morphine, , pethidine, amiloride, quinine)

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Tubular Reabsorption
Must occur when CLR < fu.GFR Reabsorption occurs all long the nephron, associated

with reabsorption of water; majority however occurring from the proximal tubules Predominantly a passive diffusion process Driven by concentration-gradient across the tubular lumen Active secretion occurs for many endogenous compounds such as vitamins, electrolytes, glucose and amino acids Urine-Plasma Ratio (U/P) based on HendersonHasselbalch equation
Influence of pKa and pH of urine

Tubular Re-absorption and Variation in Urine pH

pH changes in the urine can greatly affect

tubular re-absorption as many drugs are either weak bases or acids.

Urine pH can vary from 4.5 to 8.0 depending diet or

deliberate alteration. With acidic urine, weak acid drugs tend to be reabsorbed; with alkaline urine, weak bases are more extensively reabsorbed. The effect of pH change on tubular re-absorption can be predicted by consideration of drug pKa according to the Henderson-Hasselbalch equation.
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Ion trapping
Urine pH varies (4.5 - 8.0). Consider a barbiturate overdose. Sodium bicarbonate may be given to make the urine alkaline Urine pH 8.0 Non-ionised Rest of body pH 7.4 Non-ionised

Ionised

Ionised

Barbiturate moves into urine - eliminated from body.

How do we determine whether a drug if filtrated, or secreted of reabsorbed

How do we determine whether a drug if filtrated, or secreted

of reabsorbed

In renal clearance, if the drug is filtered but not secreted or

reabsorbed, the renal clearance of the drug will be about 120 ml/min. and/or re-absorption is occurring.

If it is less than that, then either glomerular filtration is reduced If the renal clearance is greater than 120 ml/min, then tubular

secretion must be contributing to the elimination process.

NB:
CLrenal = 0 mL/min for glucose p-aminohippuric acid (PHA) which is extensively secreted, gives a

good measure of renal plasma flow (425 to 650 mL/min).

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RENAL EXCRETION: Physicochemical Determinants

Physicochemical Determinants
molecular size (MW < 5000)

lipophilicity
ionization protein binding

renal clearance varies from 1 /min (rate of urine formation) to

70/min (rate of renal plasma flow)

gallamine: completely filtered (little protein binding)/ not

reabsorbed approach glomerular filtration rate (120 /min) or inulin clearance penicillin: complete removal by tubular secretion its clearance corresponds to renal plasma flow (700 /min) or clearance of paminohippuric acid barbiturate: highly lipid soluble reach equilibrium between plasma and urine by passive diffusion its clearance approach the rate of urine formation (1 /min) when pH's of urine and plasma equal 21

Adjustment of Maintenance Dose of Renally Cleared Drugs

For renally cleared drugs, drug excretion creatinine clearance
Creatinine clearance (ml /min) (140 age) weight (kg) 0.85 for females 72 serum creatinine (mg / dl )

Creatinine clearance ***

Creatinine is a waste product formed continuously by muscle.
Filtered by kidneys Almost no active secretion Almost no re-absorption Creatinine clearance approximately equals filtration rate (G.F.R.)

Creatinine clearance used as an estimate of G.F.R.

IMPORTANCE OF CREATININE CLERANCE The clearances of many renally excreted drugs are closely linked to GFR. e.g.. The clearance of gentamicin approximately equals GFR and therefore also approximates to creatinine clearance.

When calculating a dosage regime we can assume that gentamicin clearance will equal creatinine clearance

HEPATIC ELIMINATION

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2.2 HEPATIC ELIMINATION

Drugs and their metabolites are excreted into bile

provided that the molecular weight is greater than about 300. Hepatic elimination plays a role in the removal of conjugated metabolites particularly glucouronides
MW around 500 appears optimal for biliary excretion;

lower MW compounds are reabsorbed before leaving the bile duct.

Conjugated metabolites (i.e. glucuronides) are often of

sufficient MW for enterohepatic recycling after microbial hydrolysis of conjugate.

Examples: Conjugated morphine and chloramphenicol.
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HEPATIC ELIMINATION
Liver secretes 0.25 to 1 liter of bile each day, most of

which is reabsorbed. Bile contains bile acids (cholesterol derivatives), lipids and cholesterol, and bilirubin (a hemoglobin derivative). Bile acids are very important for absorption of fat-soluble nutrients.
The efficiency of biliary excretion system can be

assessed with bromsulphalein. As bile flows through the bile ducts it is modified by addition of a watery, bicarbonate-rich secretion from which helps neutralizes stomach acids.
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MECHANISMS OF BILIARY CLEARANCE

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Representation of drug metabolism and excretion by the hepatocyte

Biliary Excretion is Transporter Mediated

MECHANISMS OF BILIARY CLEARANCE

Determinant factors for Biliary Clearance: Physicochemical Factors

Molecular weight (400-500) Polarity Protein binding

Physiological Factors
Species Age Sex(?), pregnancy(?)

Pharmacological Factors
Chlorotoxicants Hepatotoxicants Microsomal enzyme inducers
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HEPATIC AND RENAL EXTRATION RATIO OF SOME DRUG AND METABOLITES

Extraction ratio
High Hepatic extraction Propranolol Lidocaine Nitroglycerine Morphine Intermediate Aspirine Codeine Nortriptyline Quinidine Low Diazepam Phenobarbital Phenytoin Theophylline Digoxin Furosemide Atenolol Tetracycline
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Renal extraction

Some -penicilline Some - penicilline Hippuric acid Procainamide Several Cimetidine sulphates

09-12-2010

IMPACT OF ENTEROHEPATIC RECIRCULATION ON THE DISPOSITION OF XENOBIOTICS

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Enterohepatic Circulation.
Mechanism of Enterohepatic Circulation Bile passes into the intestine where drug if lipid soluble is reabsorbed again and cycles is repeated.
Glucouronides are hydrolyzed in intestine

liberating free drugs that can be reabsorbed back

This prolongs the action the drug
e.g. morphine , ethinyl estradiol , thyroxine
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Blood Flow to the Liver and Uptake of Drugs into Hepatocytes

Extraction Ratio (ER) = Blood Flow (Cin Cout)/ (Cin)

Clearance of High Extration Drugs (ER>0.7) is blood flow dependent
Determinants of ADME 37

Hepatic Blood Flow and And Clearance of Drugs with Different ERs.

Determinants of ADME

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Drugs with High and Low Hepatic Extraction Ratios

Determinants of ADME

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PULMONARY EXCRETION

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2.3. PULMONARY EXCRETION

Major Route of

Excretion for gaseous and volatile substances, i.e anesthetics gases. Also the basis for the breathalyzer, the most common Drug Monitoring method (ethanol)
BLOOD: ALVEOLAR AIR ETHANOL = 2100:1
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Other Routes of Excretion

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2.4. Other Routes

Hair Sweat Tears Rifampin

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2.5. Dialysis (hemodialysis)

Used for patients with kidney failure. Good for drugs which:
1. 2. 3. 4.

Have good water solubility. Are not tightly bound to plasma protein. Are small (less than 500) molecular weight. Have a small apparent volume of distribution.

Question: What happens when you try to dialyze

against a large Volume of distribution (V)?

Answer: Drugs which are tightly bound or extensively stored or distributed into tissues (large V) are only poorly removed by this ROUTE.
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2.6. Mammary breast milk

Mammary minor but of possible

significance to the infant.

Diazepams: Sedation Drugs of abuse: Pediatric dependence/withdrawal Tetracycline: Permanent staining of infant teeth Chloramphenicol: Possible bone marrow suppression Propylthiouracil: Suppression of thyroid function

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Drug elimination in special population

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Drug elimination in special population

A. Drug Excretion in Children
Glomerular filtration and renal tubule function in

premature infants and newborns is somewhat immature.

GFR, normalized for body surface area, increases gradually

reaching adult values at about 6 months. Drugs which depend primarily on the renal route of elimination, such as gentamicin, ampicillin, and furosemide, have prolonged elimination times in neonates and young infants
Aminoglycosides, cephalosporins, penicillins = longer dosing interval

Age
First four days 14 days One year

GFR (ml/min/m2)
1 22 70

Adult

70

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Drug elimination in special population

B. Drug Excretion in Aging Population

The GFR declines with aging and in general is

considered part of normal aging. Decreased GFR in the elderly requires adjustment in drug dosages

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Summary of Factors affecting Drug Disposition and Responses in the Elderly

Absorption Clinical Consideration DOWN - gastric acid secretion Altered dissolution rate, possible decreased absorption rate, time of onset delayed UP - gastric pH DOWN - GI blood flow DOWN - pancreatic trypsin DOWN - GI motility DOWN - total body water DOWN - lean body weight UP - body fat (female > male) Protein Binding DOWN - serum albumin UP- gamma globulin Variable - enzyme induction UP - free fraction of acidic drugs, DOWN - free fraction of basic drugs decreased metabolism and clearance influenced by environmental factors (e.g.smoking,nutrition) Polar drugs tend to have LOWER Vd, lipid-soluble drugs HIGHER Vd Altered Physiology

Distribution Body Composition

Metabolism

Excretion

DOWN hepatic blood flow DOWN - hepatic mass VARIABLE - acetylation VARIABLE - glucuronidation DOWN - GFR DOWN- renal plasma flow DOWN - active secretion

decreased renal clearance, UP half-life

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SUMMARY

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EXCRETION PATHWAYS, TRANSPORT MECHANISMS & DRUG EXCRETED.

Excretory route Urine Mechanism GF/ ATS/ ATR, PTR Physico-chemical properties of Drug Excreted Free, hydrophilic, unchanged drugs/ metabolites of MW< 500

Bile
Lung

Active secretion
Passive diffusion

Hydrophilic, unchanged drugs/ metabolites/ conjugates of MW >500

Gaseous &volatile, blood & tissue insoluble drugs

Saliva
Milk Sweat/ skin Intestine
09-12-2010

Passive diffusion Active transport

Passive diffusion Passive diffusion Passive diffusion

Free, unionized, lipophilic drugs. Some polar drugs

Free, unionized, lipophilic drugs (basic) Free, unionized lipophilic drugs Water soluble. Ionized drugs
KLECOP, Nipani 52

QUANTIFICATION OF RATE OF ELIMINATION

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3. QUANTIFICATION OF RATE OF ELIMINATION

A. General Clearance

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Clearance
Defn: the irreversible removal of drug from the body (drug elimination) Most important PK parameter because it determines Dose & Dosing schedule. Variable parameter- affected by age, disease, genetics

Concept of Clearance
Clearance (Cl) is a measure of the efficiency with which

a drug is irreversibly removed from the body

= the volume of plasma which is completely cleared of drug per

unit time, units are ml/min, L/hr, i.e. volume per time

Clearance can be applied to an organ involved in drug

excretion although the kidney is the most important. So long as elimination is first order, clearance can be summed from various organ systems
CLT = CR + CLNR, (CLT = Total, CR = Renal, ClNR = Non-renal)

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Renal Clearance
Renal clearance is only one of other

sources of total body clearance (CLT) and has three components.

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 Drug excretion expressed as renal clearance Renal clearance (CLR): volume of plasma containing the amount of substance that is removed by the kidney in unit time

CLR =

CU * VU ---------CP

CU: drug concentration in urine VU: urine volume CP: drug concentration in plasma
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QUANTIFICATION OF RATE OF ELIMINATION.

B. Half-life

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Plasma half-life (t )
Definition is the time required for the plasma concentration of a drug to fall to half.
Is a measure of duration of action. It could be used to determine the dosing interval

Drugs

of short plasma half life Penicillin Drugs of long plasma half life Digoxin, thyroxine

Factors that may increase half-life (t )

Decreased metabolism Liver disease. Microsomal inhibitors. Decreased clearance Renal disease. Congestive heart failure. High binding of drugs Plasma proteins. Tissue binding. Enterohepatic recycling
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Pharmacokinetic Calculations Rate of elimination First order Rate =v= [Drug]Plasma k Where k is the elimination rate constant

First- Order Kinetics Drug elimination= [drug]Plasma x drug clearance The elimination rate declines as the [drug]Plasma declines Half-life and clearance remain constant if hepatic and renal function do not change

Rate= change in plasma conc /unit time= D[Drug]/min

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