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Drug ExcretionDrug Excretion

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Lecture PlanLecture Plan

1.1. Concept of drug eliminationConcept of drug elimination

2.2. Routes of EliminationRoutes of Elimination

3.3. Drug elimination in disease statesDrug elimination in disease statesRenal disease, hepatic diseaseRenal disease, hepatic disease

4.4. Quantification of rate of eliminationQuantification of rate of eliminationConcept of clearanceConcept of clearance

5.5. Drug elimination in special populationDrug elimination in special populationChildren, elderlyChildren, elderly

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1. Concept of Drug Excretion1. Concept of Drug Excretion

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2. Routes of Elimination2. Routes of Elimination

RENAL EXCRETIONRENAL EXCRETION HEPATIC and gastrointestinal excretion (feces)HEPATIC and gastrointestinal excretion (feces) PULMONARY EXCRETIONPULMONARY EXCRETIONOTHER ROUTES

Hair Tears Sweat

Dialysis (hemodialysis)Dialysis (hemodialysis) Breast milkBreast milk

RENAL EXCRETIONRENAL EXCRETION

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KIDNEY FUNCTIONKIDNEY FUNCTION

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

index of kidney function.index of kidney function.

Normal GFR in young adults it is approximately 120 - Normal GFR in young adults it is approximately 120 - 130ml/min/1.73 m130ml/min/1.73 m2 2 (<< normal body area)(<< normal body area)

A decrease precedes the onset of kidney failure.A decrease precedes the onset of kidney failure.

A persistently reduced GFR is a specific indication of A persistently reduced GFR is a specific indication of chronic kidney disease (CKD).chronic kidney disease (CKD).

Below 60 mL/min/1.73 mBelow 60 mL/min/1.73 m22 prevalence of complications prevalence of complications of CKD increases.of CKD increases.

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2.1. RENAL EXCRETION OF DRUGS2.1. RENAL EXCRETION OF DRUGS

IntroductionThe 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.

RENAL EXCRETION of drugsRENAL EXCRETION of drugs

Mechanisms of Renal disposition of drugsMechanisms of Renal disposition of drugsGlomerular filtrationGlomerular filtrationactive tubular secretionactive tubular secretion tubular re-absorptiontubular re-absorptionBiotransformationBiotransformation

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Kidney

Filtration secretion Re-absorption

Acid Base 99% of H20 +Lipid solubledrugs

Plasma flow650ml/min

Glomerular Filtration Rate (GFR)125ml/min

Urine1ml/min

Active

Nov 6, 2007 Determinants of ADME 12

Active SecretionActive Secretion Detected when the overall rate of Detected when the overall rate of

urinary drug excretion exceeds the urinary drug excretion exceeds the rate of filtrationrate of filtration

Secretory processes (proteins) Secretory processes (proteins) located predominantly within the located predominantly within the proximal tubulesproximal tubules

Mechanisms exist for secreting acids Mechanisms exist for secreting acids (anions) and bases (cations) from (anions) and bases (cations) from plasma into the tubular lumenplasma into the tubular lumen

Energy-dependentEnergy-dependentSaturable processesSaturable processesSubject to competitive Subject to competitive inhibitioninhibition

Effect of Protein-BindingEffect of Protein-BindingDepends upon secretion Depends upon secretion efficiency and contact time at efficiency and contact time at the secretory sitesthe secretory sitesRestrictiveRestrictive (dependent on the (dependent on the FFubub) vs. ) vs. Non-RestrictiveNon-Restrictive (perfusion-rate limited)(perfusion-rate limited)

RENAL EXCRETION RENAL EXCRETION ::Glomerular FiltrationGlomerular Filtration Kidney receives 1.1 L of blood (20 – 25%) of Kidney receives 1.1 L of blood (20 – 25%) of

cardiac outputcardiac output About 10% of the blood which enters the

glomerulus is filtered Compounds with Mol.wt < 20,000 filteredCompounds with Mol.wt < 20,000 filtered More than 90% of the filtrate is reabsorbed More than 90% of the filtrate is reabsorbed

(normal urinary volume is about 1 – 2 L/day). (normal urinary volume is about 1 – 2 L/day). GFR = 120 ml/minGFR = 120 ml/min CLCLRR of Inulin - a measure of GFR of Inulin - a measure of GFR

Filtered freely into the tubule Filtered freely into the tubule Not influenced by protein binding and neither secreted nor Not influenced by protein binding and neither secreted nor reabsorbedreabsorbed

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

(maximal ~ 0.11 or 10 %)(maximal ~ 0.11 or 10 %)

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RENAL EXCRETIONRENAL EXCRETION: Tubular Secretion: Tubular Secretion

In the proximal tubule there is active secretion of In the proximal tubule there is active secretion of some weak electrolyte, especially weak acids.some weak electrolyte, especially weak acids.

It requires a carrier and a supply of energy and It requires a carrier and a supply of energy and may be subject to competitive inhibition.may be subject to competitive inhibition. Tubular secretion constitute 80% renal plasmaTubular secretion constitute 80% renal plasma Carriers (competitive)Carriers (competitive)

acid pump: transport acidic drugs (aspirin, penicillin, acid pump: transport acidic drugs (aspirin, penicillin, probenicid, phenylbutazone, sulfathiazole, probenicid, phenylbutazone, sulfathiazole, frusemide, frusemide, thiazidesthiazides) and endogenous substance (uric acid) ) and endogenous substance (uric acid)     base pump: transport basic drugs (histamine, dopamine, base pump: transport basic drugs (histamine, dopamine, procaine, morphine, procaine, morphine, , pethidine, amiloride, quinine, pethidine, amiloride, quinine) )

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

with reabsorption of water; majority however with reabsorption of water; majority however occurring from the proximal tubulesoccurring from the proximal tubules

Predominantly a passive diffusion processPredominantly a passive diffusion processDriven by concentration-gradient across the Driven by concentration-gradient across the tubular lumentubular lumenActive secretion occurs for many endogenous Active secretion occurs for many endogenous compounds such as vitamins, electrolytes, compounds such as vitamins, electrolytes, glucose and amino acidsglucose and amino acids

Urine-Plasma Ratio (U/P) based on Henderson-Urine-Plasma Ratio (U/P) based on Henderson-Hasselbalch equation Hasselbalch equation

Influence of pKa and pH of urineInfluence of pKa and pH of urine

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Tubular Re-absorption and Variation in Urine pHTubular Re-absorption and Variation in Urine pH

pH changes in the urine can greatly affect pH changes in the urine can greatly affect tubular re-absorption as many drugs are either tubular re-absorption as many drugs are either weak bases or acids.weak bases or acids.

Urine pH can vary from 4.5 to 8.0 depending diet or Urine pH can vary from 4.5 to 8.0 depending diet or deliberate alteration.deliberate alteration.

With acidic urine, weak acid drugs tend to be With acidic urine, weak acid drugs tend to be reabsorbed; reabsorbed;

with alkaline urine, weak bases are more extensively with alkaline urine, weak bases are more extensively reabsorbed. reabsorbed.

The effect of pH change on tubular re-absorption can The effect of pH change on tubular re-absorption can be predicted by consideration of drug pKa according be predicted by consideration of drug pKa according to the Henderson-Hasselbalch equation. to the Henderson-Hasselbalch equation.

Ion trapping

Urine pH varies (4.5 - 8.0). Consider a barbiturate overdose. Sodium bicarbonate may be given to make the urine alkaline

Urine Rest of body pH 8.0 pH 7.4

Non-ionised Non-ionised

Ionised Ionised

Barbiturate moves into urine - eliminated from body.

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

How do we determine whether a drug if filtrated, or secreted How do we determine whether a drug if filtrated, or secreted of reabsorbedof reabsorbed In renal clearance, if the drug is filtered but not secreted or In renal clearance, if the drug is filtered but not secreted or

reabsorbed, the renal clearance of the drug will be about 120 reabsorbed, the renal clearance of the drug will be about 120 ml/min.ml/min.

If it is less than that, then either glomerular filtration is reduced If it is less than that, then either glomerular filtration is reduced and/or re-absorption is occurring. and/or re-absorption is occurring.

If the renal clearance is greater than 120 ml/min, then tubular If the renal clearance is greater than 120 ml/min, then tubular secretion must be contributing to the elimination process. secretion must be contributing to the elimination process.

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

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

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RENAL EXCRETION: RENAL EXCRETION: Physicochemical DeterminantsPhysicochemical Determinants

Physicochemical DeterminantsPhysicochemical Determinants molecular size (MW < 5000)molecular size (MW < 5000) lipophilicitylipophilicity ionizationionization protein bindingprotein binding

renal clearance varies from 1 renal clearance varies from 1 ㎖㎖ /min (rate of urine /min (rate of urine formation) to 70formation) to 70 ㎖㎖ /min (rate of renal plasma flow) /min (rate of renal plasma flow) gallamine:gallamine: completely filtered (little protein binding)/ not completely filtered (little protein binding)/ not

reabsorbed approach glomerular filtration rate (120 reabsorbed approach glomerular filtration rate (120 ㎖㎖ /min) /min) or inulin clearance or inulin clearance

penicillin:penicillin: complete removal by tubular secretion its complete removal by tubular secretion its clearance corresponds to renal plasma flow (700 clearance corresponds to renal plasma flow (700 ㎖㎖ /min) or /min) or clearance of p-aminohippuric acid  clearance of p-aminohippuric acid 

barbiturate:barbiturate: highly lipid soluble reach equilibrium between highly lipid soluble reach equilibrium between plasma and urine by passive diffusion its clearance plasma and urine by passive diffusion its clearance approach the rate of urine formation (1 approach the rate of urine formation (1 ㎖㎖ /min) when pH's /min) when pH's of urine and plasma equal of urine and plasma equal

Adjustment of Maintenance Dose of Renally Cleared Drugs

• For renally cleared drugs,

drug excretion α creatinine clearance

femalesfor 85.0)/( creatinine serum72

)(weight )age140(/min)( clearance Creatinine

dlmg

kgml

Creatinine clearance ***

Creatinine is a waste product formed continuously by muscle.

•Filtered by kidneys Creatinine clearance•Almost no active secretion approximately equals•Almost no re-absorption filtration rate (G.F.R.)

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

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

IMPORTANCE OF CREATININE CLERANCE

HEPATIC ELIMINATIONHEPATIC ELIMINATION

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2.2 HEPATIC ELIMINATION2.2 HEPATIC ELIMINATION

Drugs and their metabolites are excreted into bile Drugs and their metabolites are excreted into bile provided that the molecular weight is greater than about provided that the molecular weight is greater than about 300.300.

Hepatic elimination plays a role in the removal of Hepatic elimination plays a role in the removal of conjugated metabolites particularly glucouronidesconjugated metabolites particularly glucouronides

MW around 500 appears optimal for biliary excretion; MW around 500 appears optimal for biliary excretion; lower MW compounds are reabsorbed before leaving the lower MW compounds are reabsorbed before leaving the bile duct. bile duct.

Conjugated metabolites (i.e. glucuronides) are often of Conjugated metabolites (i.e. glucuronides) are often of sufficient MW for enterohepatic recycling after microbial sufficient MW for enterohepatic recycling after microbial hydrolysis of conjugate. hydrolysis of conjugate.

Examples: Conjugated morphine and chloramphenicol.Examples: Conjugated morphine and chloramphenicol.

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HEPATIC ELIMINATION……HEPATIC ELIMINATION……

Liver secretes 0.25 to 1 liter of bile each day, most of Liver secretes 0.25 to 1 liter of bile each day, most of which is reabsorbed. which is reabsorbed.

Bile contains bile acids (cholesterol derivatives), lipids Bile contains bile acids (cholesterol derivatives), lipids and cholesterol, and bilirubin (a hemoglobin derivative). and cholesterol, and bilirubin (a hemoglobin derivative).

Bile acids are very important for absorption of fat-soluble Bile acids are very important for absorption of fat-soluble nutrients.nutrients.

The efficiency of biliary excretion system can be The efficiency of biliary excretion system can be assessed with bromsulphalein. assessed with bromsulphalein.

As bile flows through the bile ducts it is modified by As bile flows through the bile ducts it is modified by addition of a watery, bicarbonate-rich secretion from addition of a watery, bicarbonate-rich secretion from which helps neutralizes stomach acids. which helps neutralizes stomach acids.

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MECHANISMS OF BILIARY

CLEARANCE

Representation of drug metabolism and excretion by the hepatocyte

Biliary Excretion is Transporter Mediated

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MECHANISMS OF BILIARY CLEARANCE

Determinant factors for Biliary Clearance: Physicochemical Factors

Molecular weight (400-500)PolarityProtein binding

Physiological FactorsSpeciesAgeSex(?), pregnancy(?)

Pharmacological FactorsChlorotoxicantsHepatotoxicantsMicrosomal enzyme inducers

HEPATIC AND RENAL EXTRATION RATIO OF SOME DRUG AND METABOLITES

High Intermediate Low

Hepatic extraction

PropranololLidocaineNitroglycerineMorphine

AspirineCodeineNortriptylineQuinidine

DiazepamPhenobarbitalPhenytoinTheophylline

Renal extraction

Some -penicillineHippuric acidSeveral - sulphates

Some - penicillineProcainamideCimetidine

DigoxinFurosemideAtenololTetracycline

Extraction ratio

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IMPACT OF ENTEROHEPATIC RECIRCULATION ON IMPACT OF ENTEROHEPATIC RECIRCULATION ON THE DISPOSITION OF XENOBIOTICSTHE DISPOSITION OF XENOBIOTICS

Enterohepatic Circulation….Enterohepatic Circulation….

Mechanism of Enterohepatic CirculationMechanism of Enterohepatic Circulation Bile passes into the intestine where drug if lipid Bile passes into the intestine where drug if lipid

soluble is reabsorbed again and cycles is soluble is reabsorbed again and cycles is repeated.repeated.

Glucouronides are hydrolyzed in intestine Glucouronides are hydrolyzed in intestine liberating free drugs that can be reabsorbed backliberating free drugs that can be reabsorbed back

This prolongs the action the drugThis prolongs the action the druge.g. morphine , ethinyl estradiol , thyroxinee.g. morphine , ethinyl estradiol , thyroxine

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Determinants of ADMEDeterminants of ADME 3737

Blood Flow to the Liver and Uptake of Drugs Blood Flow to the Liver and Uptake of Drugs into Hepatocytesinto Hepatocytes

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

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

Determinants of ADMEDeterminants of ADME 3838

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

Determinants of ADMEDeterminants of ADME 3939

Drugs with High and Low Hepatic Extraction Ratios

PULMONARY EXCRETION

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2.3. PULMONARY EXCRETION

Major Route of Major Route of Excretion for Excretion for gaseous and volatile gaseous and volatile substances, i.e substances, i.e anesthetics gases.anesthetics gases.

Also the basis for the Also the basis for the breathalyzer, the breathalyzer, the most common Drug most common Drug Monitoring method Monitoring method (ethanol)(ethanol)

BLOOD: ALVEOLAR AIR ETHANOL = 2100:1

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Other Routes of ExcretionOther Routes of Excretion

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2.4. Other Routes2.4. Other Routes

Hair Hair

SweatSweat

TearsRifampin

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2.5. Dialysis (hemodialysis)

Used for patients with kidney failure.

Good for drugs which: 1. Have good water solubility. 2. Are not tightly bound to plasma protein.3. Are small (less than 500) molecular weight. 4. 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 Mammary – minor but of possible significance to the infant.to the infant.

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

Drug elimination in special Drug elimination in special populationpopulation

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Drug elimination in special populationDrug elimination in special population A. Drug Excretion in ChildrenA. Drug Excretion in Children

Glomerular filtration and renal tubule function in Glomerular filtration and renal tubule function in premature infants and newborns is somewhat immature. premature infants and newborns is somewhat immature. GFR, normalized for body surface area, increases gradually GFR, normalized for body surface area, increases gradually

reaching adult values at about 6 months. reaching adult values at about 6 months. Drugs which depend primarily on the renal route of elimination, Drugs which depend primarily on the renal route of elimination,

such as gentamicin, ampicillin, and furosemide, have prolonged such as gentamicin, ampicillin, and furosemide, have prolonged elimination times in neonates and young infantselimination times in neonates and young infants

Aminoglycosides, cephalosporins, penicillins = longer dosing Aminoglycosides, cephalosporins, penicillins = longer dosing intervalinterval

Age GFR (ml/min/m2) First four days 1

14 days 22

One year 70

Adult 70

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Drug elimination in special populationDrug elimination in special population B.B. Drug Excretion in Aging Population Drug Excretion in Aging Population

The GFR declines with aging and in general is The GFR declines with aging and in general is considered part of normal aging.considered part of normal aging.

Decreased GFR in the elderly requires adjustment in Decreased GFR in the elderly requires adjustment in drug dosagesdrug dosages

Summary of Factors affecting Drug Disposition and Responses in the Elderly

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ClinicalConsideration

DOWN - gastric acid secretion

UP - gastric pHDOWN - GI blood flowDOWN - pancreatic trypsinDOWN - GI motility

Distribution

DOWN - total body water

DOWN - lean body weightUP - body fat (female > male)

DOWN - serum albumin

UP- gamma globulinVariable - enzyme induction

DOWN hepatic blood flowDOWN - hepatic massVARIABLE - acetylationVARIABLE - glucuronidationDOWN - GFRDOWN- renal plasma flowDOWN - active secretion

Altered Physiology

Absorption Altered dissolution rate, possible decreased absorption rate, time of onset delayed

Body Composition

Polar drugs tend to have LOWER Vd, lipid-soluble drugs HIGHER Vd

Protein Binding UP - free fraction of acidic drugs, DOWN - free fraction of basic drugs

Metabolism decreased metabolism and clearance influenced by environmental factors (e.g.smoking,nutrition)

Excretion decreased renal clearance, UP half-life

SUMMARYSUMMARY

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EXCRETION PATHWAYS, TRANSPORT EXCRETION PATHWAYS, TRANSPORT MECHANISMS & DRUG EXCRETED.MECHANISMS & DRUG EXCRETED.

Excretory

route

Mechanism Physico-chemical properties of Drug Excreted

Urine GF/ ATS/ ATR, PTR Free, hydrophilic, unchanged drugs/ metabolites of MW< 500

Bile Active secretion Hydrophilic, unchanged drugs/ metabolites/ conjugates of MW >500

Lung Passive diffusion Gaseous &volatile, blood & tissue insoluble drugs

Saliva Passive diffusion

Active transport

Free, unionized, lipophilic drugs. Some polar drugs

Milk Passive diffusion Free, unionized, lipophilic drugs (basic)

Sweat/ skin

Passive diffusion Free, unionized lipophilic drugs

Intestine Passive diffusion Water soluble. Ionized drugs09-12-2010 52KLECOP, Nipani

QUANTIFICATION OF RATE OFQUANTIFICATION OF RATE OFELIMINATIONELIMINATION

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3. QUANTIFICATION OF RATE OF3. QUANTIFICATION OF RATE OFELIMINATIONELIMINATION

A. General Clearance

ClearanceClearance

Def’n: Def’n: the irreversible removal of drug from the the irreversible removal of drug from the

bodybody (drug elimination)(drug elimination)Most important PK parameter because it Most important PK parameter because it

determines determines DoseDose & & Dosing scheduleDosing schedule..Variable parameterVariable parameter- affected by age, - affected by age,

disease, genetics …disease, genetics …

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Concept of ClearanceConcept of Clearance

Clearance (Cl) is a measure of the efficiency with which Clearance (Cl) is a measure of the efficiency with which a drug is irreversibly removed from the body a drug is irreversibly removed from the body = the volume of plasma which is completely cleared of drug per = the volume of plasma which is completely cleared of drug per

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

Clearance can be applied to an organ involved in drug Clearance can be applied to an organ involved in drug excretion although the kidney is the most important.excretion although the kidney is the most important.

So long as elimination is first order, clearance can be So long as elimination is first order, clearance can be summed from various organ systemssummed from various organ systems

CLT = CR + CLNR, CLT = CR + CLNR, (CLT = Total, CR = Renal, ClNR = Non-renal) (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.

Drug excretion expressed as renal clearance Drug excretion expressed as renal clearance Renal clearance (CLR): volume of plasma containing the Renal clearance (CLR): volume of plasma containing the

amount of substance that is removed by the kidney in unit amount of substance that is removed by the kidney in unit time time

                                      CU * VU           CU * VU           CLR =CLR = ----------       ----------       

CP                   CP                  

CU: drug concentration in urineCU: drug concentration in urineVU: urine volumeVU: urine volumeCP: drug concentration in plasma CP: drug concentration in plasma

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QUANTIFICATION OF RATE OFELIMINATION……….

B. Half-life

Plasma half-life (t ½)Plasma half-life (t ½)DefinitionDefinition

is the time required for the plasma is the time required for the plasma concentration of a drug to fall to half.concentration of a drug to fall to half.

Is a measure of duration of action.Is a measure of duration of action.

It could be used to determine the dosing intervalIt could be used to determine the dosing interval

Drugs of short plasma half life Drugs of short plasma half life PenicillinPenicillin

Drugs of long plasma half life Drugs of long plasma half life Digoxin, thyroxineDigoxin, thyroxine

Factors that may increase half-life Factors that may increase half-life (t ½ )(t ½ )

Decreased metabolismDecreased metabolismLiver disease.Liver disease.Microsomal inhibitors.Microsomal inhibitors.

Decreased clearanceDecreased clearanceRenal disease.Renal disease.Congestive heart failure.Congestive heart failure.

High binding of drugsHigh binding of drugsPlasma proteins.Plasma proteins.Tissue binding.Tissue binding.

Enterohepatic recyclingEnterohepatic recycling

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Pharmacokinetic CalculationsRate of eliminationFirst orderRate =v= [Drug]Plasma kWhere k is the elimination rate constant

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

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

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