Pharmacokinetics / Biopharmaceutics - Drug Elimination

Drug Elimination

• Drugs are removed from the body by various elimination processes.

• Drug elimination refers to the irreversible removal of drug from thebody by all routes of elimination.

• Drug elimination is usually divided into two major components:excretion and biotransformation.

Drug Elimination

•Drug excretion is the removal of the intact drug.

•Nonvolatile drugs are excreted mainly by renalexcretion, a process in which the drug passes throughthe kidney to the bladder and ultimately into theurine.

•Other pathways for drug excretion may include theexcretion of drug into bile, sweat, saliva, milk (vialactation), or other body fluids.

Drug Elimination

•Volatile drugs, such as gaseous anesthetics or drugswith high volatility, are excreted via the lungs intoexpired air.

•Biotransformation or drug metabolism is theprocess by which the drug is chemically convertedin the body to a metabolite.

•Biotransformation is usually an enzymatic process.

Drug Elimination

•A few drugs may also be changed chemically by anon-enzymatic process (eg, ester hydrolysis).

•The enzymes involved in the biotransformation ofdrugs are located mainly in the liver.

•Other tissues such as kidney, lung, small intestine,and skin also contain biotransformation enzymes.

Pathways of Drug Biotransformation

•Pathways of drug biotransformation may be divided intotwo major groups of reactions:

I. Phase I:• Are those in which polar functional groups are introduced in the molecule or unmasked by

oxidation, reduction, and hydrolysis.

II. Phase II:• Are those in which the functional groups of the original drug (or metabolite formed in a

phase I reaction) are masked by a conjugation reactions.

• Most phase II conjugates are very polar, resulting in rapid drug elimination from the body.


• In most cases the metabolite is formed byproduction of a more polar group, Generally theresultant metabolite is more water soluble, andcertainly less lipid soluble. Less drug is reabsorbedfrom the kidney.

•Occasionally the metabolite is less water soluble.• An example: Some of the earlier sulfonamides are

acetylated to relatively insoluble metabolites whichprecipitated in urine, crystalluria.


• In most cases the metabolites are inactive.

• Occasionally the metabolite is also active.

• The original drug may take on the role of a pro-drug. For example:-• amitriptyline ---> nortriptyline• codeine ---> morphine• primidone ---> phenobarbital

• Drug metabolism can be quantitatively altered by druginteractions. This alteration can be an increase by induction ofenzyme activity or a reduction by competitive inhibition.

Pharmacological Activity of metabolitesActive Drug to Inactive metabolite

Amphetamine Phenylacetone

Phenobarbitol Hydroyphenobarbitol

Active Drug to Active metabolite

Phenacetin Acetaminophen

Amitryptyline Nortryptyline

Active Drug to Active metabolite with different pharmacological Activity

Mepiridine(analgesic)

Normeperidine(CNS Stimulant)

Prodrug Drug to Active metabolite

Chlorazepate Nordiazepam

Hetacillin Ampicillin

Active Drug to Reactive metabolite

Acetaminophen Reactive metabolite (Hepatotoxicity)

Methoxyflurane Reactive metabolite(Renal toxicity)

First-Order Elimination

• The rate constant of elimination (k) is the sum of the first-order rateconstant for metabolism (km) and the first-order rate constant forexcretion (ke):

me kkk

Renal Drug Excretion

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

• Renal excretion is a major route of elimination for many drugs.

• Drugs that are nonvolatile, water soluble, have a low molecular weight (MW), orare slowly biotransformed by the liver are eliminated by renal excretion.

• The processes by which a drug is excreted via the kidneys may include anycombination of the following:

•Glomerular filtration.•Active tubular secretion.• Tubular reabsorption.

Diagram: One Nephron of the Kidney


Glomerular Filtration:

• It is a passive process by which small molecules and drugs arefiltered through the glomerulus of the nephron.

•Drugs bound to plasma proteins are too large to be filtered atthe glomerulus.

•Drugs such inulin are not actively secreted or reabsorbed.They are used to measure the glomerular filtration rate (GFR)

• Creatinine is used clinically to assess GFR


Active Tubular Secretion

• It is carrier –mediated active transport system thatrequires energy.

•Two Active tubular secretion pathways exist in thekidney: one system for weak acids and one systemfor weak bases.


•Active tubular secretion shows competition effects.• For example, probenecid (a weak acid) competes for the

same system as penicillin, decreasing the rate of penicillinexcretion.


Tubular Reabsorption

• It is a passive process that follows Fick`s law ofdiffusion.

• Lipid-soluble drugs are reabsorbed from the lumenof the nephron back into the systemic circulation.


•For weak electrolyte drugs, urine pH affect the ratioof non-ionized and ionized drug:

a) If the drug exists primarily in the non-ionized orlipid-soluble form, then it is reabsorbed moreeasily from the lumen of the nephron.

b) If the drug exists primarily in the ionized orwater-soluble form, then it is excreted moreeasily in urine.


c) Depending on the pKa of the drug, alteration of theurine pH alters the ratio of ionized to non-ionized drugand affects the rate of drug excretion. For example,alkalinization of the urine by the administration ofsodium bicarbonate increases the excretion ofsalicylates (weak acid).

•An increase in urine flow caused by simultaneousadministration of a diuretic decrease the time for drugreabsorption. Consequently more drug is excreted.


• renal clearance may be considered as the ratio ofthe sum of the glomerular filtration and activesecretion rates less the reabsorption rate divided bythe plasma drug concentration:

P

RC

Clrateon reabsorptiratesecretion rate filtration

Drug Clearance

•Drug clearance (body clearance, total body clearance,or Cl T) is a pharmacokinetic term for describing drugelimination from the body without identifying themechanism of the process.

• calculate clearance based on plasma drugconcentration data.

min//

min//

)(Cion concentrat plasma

raten eliminatio

P

mlmlg

g

C

dtdDCl

Cl

P

ET

T

Where: DE is the amount of drug eliminated.dDE/dt is the rate of elimination.

Drug Clearance

• Clearance is the product of V D and k, both of which are constant.

• As the plasma drug concentration decreases during elimination,the rate of drug elimination, dDE/dt, decreases accordingly, butclearance remains constant.

• Clearance is constant as long as the rate of drug elimination is afirst-order process.

D

P

DPT kV

C

VkCCl

Example

•Penicillin has a Cl T of 15 mL/min. Calculate theelimination rate for penicillin when the plasma drugconcentration, C p, is 2μg/mL.

• Thus, 150 μg/min of penicillin is eliminated from the bodywhen the plasma penicillin concentration is 10 μg/mL.

Solution

min/30min/15/2 gmlmlgdt

dDE

Drug Clearance

•Clearance may be used to estimate the rate of drugelimination at any given concentration.

•Using the previous example, if the elimination rateof penicillin was measured as 150 μg/min when theplasma penicillin concentration was 10 μg/mL, thenthe clearance of penicillin is calculated:

min/15/10

min/150g

mlg

gClpenicillin

Drug Clearance

• The elimination rate constant (k) represents the sum totalof all the rate constants for drug elimination, includingexcretion and biotransformation.

• ClT is the sum total of all the clearance processes in thebody, including clearance through the kidney (renalclearance), lung, and liver (hepatic clearance).

Example

•Determine the total body clearance for a drug in a 70-kgmale patient. The drug follows the kinetics of a one-compartment model and has an elimination half-life of 3hours with an apparent volume of distribution of 100 mL/kg.

Solution

hrmlkgkghrmlCl

kghrmlkgmlhrCl

hrt

k

T

T

/161770/1.23

patient, 70kg aFor

/1.23/100231.0

231.03

693.0693.0

1

1

2/1

Hepatic Clearance

•Hepatic clearance may be defined as the volume ofblood that perfuses the liver and is cleared of drug perunit of time.

•Total body clearance is composed of all the clearancesin the body.

•Where:• ClT is total body clearance.

• Clnr is nonrenal clearance (often equated with hepaticclearance, Clh).

• Clr is renal clearance.

rnrT ClClCl

Hepatic Clearance

•Hepatic clearance (Clh) is also equal to total bodyclearance (ClT) minus renal clearance (ClR) assumingno other organ metabolism

• Where: fe = percent of intact drug recovered in the urine.

RTh ClClCl

)1( eTh fClCl

Hepatic Clearance

• The total body clearance of a drug is 10 mL/min/kg. Therenal clearance is not known. From a urinary drug excretionstudy, 60% of the drug is recovered intact and 40% isrecovered as metabolites. What is the hepatic clearance forthe drug, assuming that metabolism occurs in the liver?

kgmlCl

fClCl

h

eTh

min//4)6.01(10

)1(

First-Pass Effects

•For some drugs, the route of administration affectsthe metabolic rate of the compound.

•For example, a drug given parenterally,transdermally, or by inhalation may distributewithin the body prior to metabolism by the liver.

• In contrast, drugs given orally are normallyabsorbed in the duodenal segment of the smallintestine and transported via the mesenteric vesselsto the hepatic portal vein and then to the liverbefore entering the systemic circulation.

First-Pass Effects

•Drugs that are highly metabolized by the liver or bythe intestinal mucosal cells demonstrate poorsystemic availability when given orally. This rapidmetabolism of an orally administered drug beforereaching the general circulation is termed first-passeffect or presystemic elimination.

•Example:• 40 mg propranolol given by oral route is equivalent to 2 mg

I.V. administration.• morphine p.o. 30 mg & IV. 5 mg • lidocaine not active p.o.

First-Pass Effects

•The AUC for a drug given orally is less than the AUC forthe same dose of drug given intravenously.

•The absolute bioavailability (F) may reveal evidence ofdrug being removed by the liver due to first-pass effectsas follows:

•Drugs such as propranolol, morphine, and nitroglycerinhave F values less than 1 because these drugs undergosignificant first-pass effects.

IVIV

oraloral

DAUC

DAUCF

,0,0

,0,0

/

/

Physiologic/Organ Clearance

•For any organ, clearance may be defined as the fractionof blood volume containing drug that flows through theorgan and is eliminated of drug per unit time.

•From this definition, clearance is the product of theblood flow (Q) to the organ, and the extraction ratio(ER). The ER is the fraction of drug extracted by theorgan as drug passes through.

)(ERQClearance


• If the drug concentration in the blood (Ca) entering theorgan is greater than the drug concentration of blood(Cv) leaving the organ, then some of the drug has beenextracted by the organ

•ER is a ratio with no units. The value of ER may rangefrom 0 (no drug removed by the organ) to 1 (100% of thedrug is removed by the organ).

a

va

C

CCER


•An ER of 0.25 indicates that 25% of the incoming drugconcentration is removed by the organ as the drug passesthrough.

• The physiologic approach to clearance shows that clearancedepends on the blood flow rate and the ability of the organ toeliminate drug, whereas the classical definitions of clearance isthat a constant or static fraction of the volume in which thedrug is contained is removed per unit time by the organ.

a

va

C

CCQERQClearance )(

Liver Extraction Ratio

• Because there are many other reasons for a drug to have areduced F value, the extent of first-pass effects is not veryprecisely measured from the F value.

• The liver extraction ratio (ER) provides a direct measurementof drug removal from the liver after oral administration of adrug.

a

va

C

CCER

Where: Ca is the drug concentration in the blood entering the liver Cv is the drug concentration leaving the liver.

Liver Extraction Ratio

•Because Ca is usually greater than Cv, ER is usuallyless than 1.

•For example, for propranolol, ER or [E] is about0.7—that is, about 70% of the drug is actuallyremoved by the liver before it is available forgeneral distribution to the body.

•By contrast, if the drug is injected intravenously,most of the drug would be distributed beforereaching the liver, and less of the drug would bemetabolized.

Relationship between Absolute Bioavailability and Liver Extraction•The following relationship between bioavailability and

liver extraction:

• Where: F is the fraction of bioavailable drug.ER is the drug fraction extracted by the liver,

F″ is the fraction of drug removed by non-hepatic process.

• If F″ is assumed to be negligible—that is, there is no loss ofdrug due to chemical degradation, gut metabolism, andincomplete absorption—ER may be estimated from:

FERF 1

Relationship between Absolute Bioavailability and Liver Extraction

ERF 1

IVIV

oraloral

DAUC

DAUCER

,0,0

,0,0

/

/1

Estimation of Reduced Bioavailability Due to Liver Metabolism and Variable Blood Flow

•Blood flow to the liver plays an important role in theamount of drug metabolized after oral administration.

•Changes in blood flow to the liver may substantially alterthe percentage of drug metabolized and therefore alterthe percentage of bioavailable drug.

•The relationship between blood flow, hepatic clearance,and percent of drug bioavailable is:

• Where: Clh is the hepatic clearance of the drugQ is the effective hepatic blood flow.

F' is the bioavailability factor obtained fromestimates of liver blood flow and hepatic

clearance, ER.

•The hepatic blood flow may vary from 1 to 2 L/mindepending on diet, food intake, physical activity ordrug intake.

ERQ

ClF h 11



•For the drug propoxyphene hydrochloride, F' hasbeen calculated from hepatic clearance (990mL/min) and an assumed liver blood flow of 1.53L/min:

•The results, showing that 35% of the drug issystemically absorbed after liver extraction.

35.053.1

99.01 F

• first-pass effect is a very important consideration fordrugs that have a high extraction ratio.

•Drugs with low extraction ratios, such as theophylline,have very little presystemic elimination, asdemonstrated by complete systemic absorption afteroral administration.

• In contrast, drugs with high extraction ratios havepoor bioavailability when given orally.


•Therefore, the oral dose must be higher than theintravenous dose to achieve the same therapeuticresponse.

• In some cases, oral administration of a drug with highpresystemic elimination, such as nitroglycerin, may beimpractical due to very poor oral bioavailability, andthus a sublingual, transdermal, or nasal route ofadministration may be preferred.


•To overcome first-pass effect, the route ofadministration of the drug may be changed.

• For example, nitroglycerin may be given sublingually ortopically, and xylocaine may be given parenterally to avoidthe first-pass effects.

•Another way to overcome first-pass effects is to eitherenlarge the dose or change the drug product to amore rapidly absorbable dosage form.


•A change in liver blood flow may alter hepatic clearance andF'.

•A large blood flow may deliver enough drug to the liver toalter the rate of metabolism.

• In contrast, a small blood flow may decrease the delivery ofdrug to the liver and become the rate-limiting step formetabolism.

• The hepatic clearance of a drug is usually calculated fromplasma drug data rather than whole-blood data.


•Factors that affect the hepatic clearance of a druginclude:

1) Blood flow to the liver.2) Intrinsic clearance.3) The fraction of drug bound to protein.

Relationship between Blood Flow, Intrinsic Clearance, and Hepatic Clearance

a

vah

C

CCQERQCl )(

•An increase in blood flow to the liver will increasethe rate of drug removal by the organ.

•Propranolol, a β-adrenergic blocking agent,decreases hepatic blood flow by decreasing cardiacoutput. In such a case, the drug decreases its ownclearance through the liver when given orally.


• Intrinsic clearance (Clint) describes the total ability of the liver tometabolize a drug independently of blood flow.

• Intrinsic drug clearance primarily occurs because of inherent abilityof the biotransformation enzymes (mixed-function oxidases) tometabolized the drug as it enters the liver.

• Levels of these enzymes are increased by various drugs (e.g,phenobarbital) and environmental agents (e.g, tobacco smoke).

• These enzymes are inhibited by other drugs and environmentalagents (e.g, cimetidine, acute lead poisoning)


Sources of variation in intrinsic clearance

• Genetic factors.

• Genetic differences within population.

• Racial differences among different population.

• Environmental factors and drug interactions:• Enzyme induction.

• Enzyme inhibition.

• Physiological conditions:• Age.

• Gender.

• Diet / Nutrition.

• Pathophysiology.

• Drug dosage regimen.

• Route of drug administration.

•Hepatic clearance is a concept for characterizing drugelimination based on both blood flow and the intrinsicclearance of the liver, as shown in Eq.


int

int

ClQ

ClQClh


•The hepatic clearance of drugs that have highextraction ratios and high Clint values (e.g,propranolol) is most affected by changes in bloodflow and inhibitors of the drug metabolismenzymes.

•The hepatic clearance of drugs that have lowextraction ratios and low Clint values (e.g,theophylline) is most affected by changes in Clintand is affected only slightly by changes in hepaticblood flow.

Biliary Drug Excretion

•Biliary drug excretion, an active transport process, isalso included in hepatic clearance.

•Separate active secretion systems exist for weak acidsand weak bases.

•Drugs that are excreted in bile are usually high-molecular- weight compounds(i.e., M. wt . More than500) or polar drugs, such as reserpine, digoxin, andvarious glucuronide conjugates.


•An average bile flow of 0.5–0.8 mL/min in humans,biliary clearance can be calculated if the bileconcentration, C bile, is known:

•Drugs may be recycled by the enterohepaticcirculation.

P

bilebiliary

C

CCl

flow bile


Enterohepatic recirculation of bile acids and drug.


• Some drugs are absorbed from GIT through the mesentericand hepatic portal veins, proceeding to the liver.

• The liver may secrete some of the drug (unchanged or as aglucuronide metabolite) into the bile.

• From the bile (stored in the gallbladder), the drug mayempty into the GIT through the bile duct.

• if the drug is a glucuronide metabolite, bacteria in the GITmay hydrolyze the glucronide moiety, allowing the releaseddrug to be reabsorbed.

Homework # 6• A drug fitting a one-compartment model was found to be

eliminated from the plasma by the following pathways with thecorresponding elimination rate constants.• Metabolism: km = 0.200 hr–1

• Kidney excretion: ke = 0.250 hr–1

• Biliary excretion: kb = 0.150 hr–1

a) What is the elimination half-life of this drug?

b) What would be the half-life of this drug if biliary secretionwere completely blocked?

c) What would be the half-life of this drug if drug excretionthrough the kidney were completely impaired?

d) If drug-metabolizing enzymes were induced so that the rateof metabolism of this drug doubled, what would be the newelimination half-life?

• A new broad-spectrum antibiotic was administered by rapid intravenous injection to a 50-kg woman at a dose of 3 mg/kg. The apparent volume of distribution of this drug was equivalent to 5% of body weight. The elimination half-life for this drug is 2 hours.

• a. If 90% of the unchanged drug was recovered in the urine, what is the renal excretion rate constant?

• b. Which is more important for the elimination of this drug, renal excretion or biotransformation? Why?

• Calculate the hepatic clearance for a drug with an intrinsic clearance of 40 mL/min in a normal adult patient whose hepatic blood flow is 1.5 L/min.

• a. If the patient develops congestive heart failure that reduces hepatic blood flow to 1.0 L/min but does not affect the intrinsic clearance, what is the hepatic drug clearance in this patient?

• b. If the patient is concurrently receiving medication, such as phenobarbital, which increases the Clint to 90 mL/min but does not alter the hepatic blood flow (1.5 L/min), what is the hepatic clearance for the drug in this patient?

• Calculate the hepatic clearance for a drug with an intrinsic clearance of 12 L/min in a normal adult patient whose hepatic blood flow is 1.5 L/min. If this same patient develops congestive heart failure that reduces his hepatic blood flow to 1.0 L/min but does not affect intrinsic clearance, what is the hepatic drug clearance in this patient?

• a. Calculate the extraction ratio for the liver in this patient before and after congestive heart failure develops.

• b. From the above information, estimate the fraction of bioavailable drug, assuming the drug is given orally and absorption is complete.

• A drug is being screened for antihypertensive activity. After oral administration, the onset time is 0.5 to 1 hour. However, after intravenous administration, the onset time is 6 to 8 hours.a. What reasons would you give for the differences in the onset times for oral and intravenous drug administration?

• The hepatic intrinsic clearance of two drugs are as follows:

• Drug A: 1300 mL/min

• Drug B: 26 mL/min

• Which drug is likely to show the greatest increase in hepatic clearance when hepatic blood flow is increased from 1 L/min to 1.5 mL/min? Which drug will likely be blood-flow limited?

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Pharmacokinetics / Biopharmaceutics - Drug Elimination