babbini fm03 fm03x drug elimination 14 sum

M. Babbini, MD, PhD Pharmacokinetics: Drug Elimination

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PHARMACOKINETICS

Drug Elimination

Learning Objectives

-Define the term "clearance of a drug." -Describe the main features of drug clearance-Define the term "drug biotransformation".-Explain the consequences of biotransformation with respect to the pharmacological activity of the drug.-List the main categories of drug biotransformation reactions.-Describe the main features of oxidation reactions.-Describe the main features of glucuronic acid conjugation.-Illustrate the main features of microsomal and non-microsomal drug metabolizing enzymes.-Give examples of drugs that can induce or inhibit drug metabolizing enzymes.-Explain the consequences of drug induction or inhibition of microsomal enzymes.-List the most important primary factors affecting drug biotransformation.-List the main excretion routes of drugs.-Describe the main features of glomerular filtration, tubular reabsorption and tubular secretion of a drug.-Explain how glomerular filtration rate can affect the renal clearance of a drug-Calculate the total, the hepatic and the renal clearance of a drug, given sufficient data.-Explain how a change in urine pH can change the renal clearance of a drug.-Describe the main features of the biliary excretion of drugs.

DRUG ELIMINATION

-Drug elimination includes the following two different processes:

1) Biotransformation (when biotransformed, the drug is no longer present as such in the body)

2) Excretion (the drug is transported outside the body by the kidney and other organs)

-The pharmacokinetic parameter that gives a quantitative measure ofdrug elimination is named clearance.


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THE CLEARANCE OF A DRUG *

-The Clearance (CL) of a drug is defined as the volume of a biologicalfluid (generally plasma) from which that drug is removed ("cleared") perunit time (usually per minute or per hour).

-Elimination of drug from the body may involve processes occurring inkidney, liver, and other organs. Clearance can be described in terms of

h rthe eliminating organ: hepatic clearance (CL ) renal clearance,(CL )

oclearance of other organs (CL ).

tThen, total systemic clearance (CL ) is given by:

t h r oCL = CL + CL + CL

-Clearance may be described in terms of renal excretion and eliminationby all other processes, (e.g. renal CL and non-renal CL) or in terms ofthe nature of the elimination processes (e.g metabolic CL or excretoryCL).

-For drugs eliminated with first order kinetics clearance is a constant(i.e. the same fraction of the plasma concentration of the drug is clearedper unit time).

-The magnitude of clearance of a given organ for different drugs canrange from a small fraction of the organ blood flow to the maximumblood flow of that organ.


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DRUG BIOTRANSFORMATION

-Drugs are generally foreign compounds (xenobiotics) and thereforeare, as a rule, eliminated from the body in order to maintainhomeostasis.

-Renal excretion plays a major role in eliminating water-solublesubstances. Since many drugs are not water soluble,biotransformation is the way to turn drugs into more polar, andhence more readily excretable, products.

-Drug biotransformation takes place mainly in the liver and (to a lesserextent in the lung, kidney and intestine).

-Biotransformation reactions can be grouped into two categories(phase I and phase II reactions). Drugs may undergo only phase I oronly phase II biotransformation, or phase I followed by phase II.

-The only feature common to all these reactions is that the products ofbiotransformation are more water soluble than the original drug.

BIOLOGIC SIGNIFICANCE OF DRUG BIOTRANSFORMATION

Outcomes ofbiotransformation

Biological significance

Inactivation An active drug is converted to an inactive product(the most frequent case)

Maintenance ofactivity

An active drug is converted into another activesubstance (active metabolite). Its activity can be:

a) equal to (or less or more pronounced than) thatof the parent compound (in any case the duration ofthe pharmacological effect is increased).

b) qualitatively different from that of the parentcompound (this may lead to toxic metabolites).

Activation An inactive precursor (prodrug) is converted into apharmacologically active drug.


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DRUG BIOTRANSFORMATION REACTIONS

PHASE I REACTIONS (nonsynthetic reactions)

Oxidations-Oxygen is added to a compound or the proportion of oxygen in acompound is increased by removal of other groups

Reductions-Oxygen is removed from a compound or the proportion of oxygen in acompound is decreased by addition of other groups

Hydrolyses-A compound is cleaved by addition of water

PHASE II REACTIONS (synthetic reactions)

Conjugations-Drugs are conjugated to a molecule provided by the body, (glucuronicacid, acetyl groups, methyl groups, sulphate, etc.). Main conjugation reaction are:

Glucuronidation (conjugation with glucuronic acid) Acetylation (conjugation with acetyl groups) Methylation (conjugation with methyl groups) Sulfation (conjugation with sulphate)


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OXIDATION REACTIONS

-The reactions are catalyzed by microsomal enzymes (mixed functionoxidases or monooxygenases) and also by non microsomal enzymes(alcohol dehydrogenase, xanthine oxidase, etc.).

-Two main monooxygenases are the NADPH-cytochrome P450reductase (a flavoprotein) and the cytochrome P450 (a hemoprotein)that serves as the terminal oxidase. The activity of these enzymesrequires a reducing agent (NADPH) and molecular oxygen.

-Oxidative reactions may lead to highly reactive intermediates(epoxides, free radicals, etc.) that can combine covalently with cellconstituents causing such problems as tissue necrosis, blooddyscrasias, teratogenesis, carcinogenesis or fetal death.

GLUCURONIDATION

-Glucuronidation is the most common conjugation reaction ofxenobiotics.

-Glucuronic acid (a product of carbohydrate metabolism) can beconjugated with compounds of the general type R-OH, R-COOH,

2R-NH , R-SH.

-Glucuronidation occurs mainly in the liver and is catalyzed by amicrosomal enzyme named UDP-glucuronosyltransferase.

-Glucuronosyltransferase activity can be very low in some cases andthis may have pathological consequences.

-The glucuronoconjugated drug is more water soluble than the parentcompound and, but in exceptional cases, pharmacologically inactive.

-Glucuronide conjugates may be excreted with the bile, hydrolyzed inthe intestine by a beta-glucuronidase, and reabsorbed.


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MICROSOMAL DRUG-METABOLIZING ENZYMES

-Microsomal enzymes are located mainly in the smooth endoplasmicreticulum (SER) of liver cells (and, to a lesser extent, in the SER ofother organs).

-The substrate specificity of microsomal enzymes is very low and theyhave poor catalytic efficiency that is however compensated by theirabundance.

-Microsomal enzymes are mainly monooxygenases devoted tobiotransformation of xenobiotics and can only catalyze reaction ofcompounds that are lipid soluble.

-The products of enzymatic reaction are almost always more watersoluble than the original substrates.

-Microsomal enzymes catalyze mainly oxidations andglucuronidations.

-Different cytochrome P450 isozymes have been identified. Thecytochrome P450 1, 2 and 3 gene families (CYP1A2, CYP2C9,CYP2C19, CYP3A4) encode the enzymes involved in the majority of alldrug biotransformation. Some of these families exhibit geneticpolymorphism.

- Microsomal enzymes can be induced or inhibited by many drugs andenvironmental pollutants (see below).


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ENZYME INDUCTION AND INHIBITION BY DRUGS

Enzyme induction-Induction results from increased synthesis of cytochrome P450dependent enzymes in the liver. Inducing drugs may selectively inducedifferent families of CYP450.

-Several days of treatment with inducing drug are usually required toreach maximum induction, as well as to regress after the withdrawal ofthe inducer.

-Some drugs can induce their own biotransformation.

Enzyme inhibition- Activity of different families of CYP450 can be inhibited (reversibly orirreversibly) by several drugs (see below)


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DRUGS THAT SIGNIFICANTLY INDUCE OR INHIBIT DRUG METABOLIZING ENZYMES

CYP family Inducers Inhibitors

1A2 BarbituratesRifampinOmeprazole

CimetidineAmiodaroneSelective Serotonin Reuptake InhibitorsFluoroquinolonesMacrolides Grapefruit juice

2C9 BarbituratesRifampin

Cimetidine AmiodaroneSelective Serotonin Reuptake InhibitorsMetronidazole

2C19 Barbiturates RifampinPhenytoin Carbamazepine

CimetidineSelective Serotonin Reuptake InhibitorsOmeprazole

2D6 Rifampin CimetidineAmiodaroneSelective Serotonin Reuptake InhibitorsHIV protease inhibitors

3A4 * BarbituratesRifampinPhenytoinCarbamazepineCorticosteroids

CimetidineAmiodaroneSelective Serotonin Reuptake InhibitorsFluoroquinolonesMacrolidesMetronidazoleGrapefruit juice (high doses)HIV protease inhibitors

* This isoenzyme is responsible for the metabolism of 50% of all drugs.


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NON-MICROSOMAL DRUG-METABOLIZING ENZYMES

-They are located mainly in cytosol or mitochondria of various cells(mainly liver cells) and also in extracellular fluids (e.g. plasma).

-The substrate specificity of these enzymes is variable (generallymoderate).

- the synthesis of some non-microsomal drug-metabolizing enzymes isunder genetic control.

-The products of enzymatic reaction are almost always more watersoluble than the original substrates.

-Non-microsomal enzymes catalyze mainly conjugations (exceptglucuronidation), hydrolyses and some oxidations and reductions.

-Non-microsomal enzymes can be inhibited (competitively or noncompetitively) but cannot be induced by xenobiotics.


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FACTORS AFFECTING DRUG BIOTRANSFORMATION

Individualdifferences

From some drugs there can be a 30-fold variation inthe rate of biotransformation among differentindividuals.

Age Glucuronide formation reaches adult valuesbetween the 3rd and the 4th years of life. Monooxygenase activity is low in the newborn and inthe aged.

Nutrition an diet Protein and essential fatty acid deficiency impairsdrug biotransformation.

Genetic factors Deficiency of acetylating enzyme (which metabolizesisoniazid, procainamide, etc.) is inherited as anautosomal recessive trait. Individuals with this trait(slow acetylators) occur in more than 50% ofCaucasians but only in 10% of Asians.P450 isozymes show genetic polymorphism anddifferent subgroups have been characterized aspoor, intermediate, extensive and ultra rapidmetabolizers. In the case of CYP2C9 (whichmetabolizes warfarin) 3% of Caucasians, but morethan 20% of Asians are poor metabolizers.

Drug-druginteractions

(See above enzyme induction and inhibition bydrugs)

Diseases Hepatic, cardiac, endocrine, and pulmonarydiseases can impair drug biotransformation.


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DRUG EXCRETION

Route Notes

Renal It is the most important route for excretion of drugsand their metabolites.

Intestinal Biliary excretion(for some drugs and many drug metabolites)

Fecal excretion (for drugs not crossing the gut wall)

Pulmonary For gases or volatile drugs.

Others Saliva, sweat, skin sebum, tears, nasopharyngealsecretions, bronchial secretions, milk.

GLOMERULAR FILTRATION OF DRUGS

-Approximately 125 (± 26) ml of plasma water is filtered across theporous glomerular capillary membrane each minute.

-All drugs which are free in plasma water will be filtered as long astheir molecular size, charge and shape are not excessively large.

-Filtration rate of these drugs is mainly dependent upon the hydrostaticpressure in the glomerular capillaries.

-Drugs bound to plasma proteins or with a MW greater than 65000(that is with a molecular diameter of about 8 nm) will not be filtered.

-Since only the unbound drug undergoes glomerular filtration, drugswhich are tightly bound to plasma proteins may remain in plasma fora long time.

(It is worth to note that since the drug fraction bound to plasma proteinsis in equilibrium with the free drug fraction, and the percent binding isconstant, even drugs extensively bound to plasma proteins will betotally eliminated, sooner or later, by the kidney):


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TUBULAR REABSORPTION OF DRUGS

-Drug reabsorption occurs all along the nephron, associated with thereabsorption of water filtered at the glomerulus.

-Drug reabsorption occurs mainly by lipid diffusion (active reabsorptionmay occur for many endogenous compounds including vitamins,electrolytes, glucose and amino acids).

-The membrane of the tubular cells acts as a lipoidal barrier toreabsorption. Therefore the degree of reabsorption of a drug willdepend mainly on:

1) the physicochemical properties of the drug (molecular weight,lipid-solubility, ionization).2) the pH of the tubular urine.

-Since the pH of tubular urine can vary widely (from 4.5 to 8), trappingof drug in the urine may occur.

TUBULAR SECRETION OF DRUGS

-Drug secretion occurs in the proximal tubule, mainly by activetransport.

-Two secretory systems, one for organic anions (acids), the otherfor organic cations (bases), actively transfer endogenous compoundsand drugs from blood to luminal fluid.

-A striking feature of this active secretion is the variety of chemicalstructures that are transported (i.e. the transport system specificity isvery low).

-Within each system, drugs can compete with one another forsecretion (there is however no competition across systems, i.ebetween acids and bases).

-Active tubular secretory systems are incompletely developed in the newborn infant and their functional capacity may be diminished in theelderly.


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EXAMPLES OF DRUGS AND DRUG METABOLITES, ACTIVELY SECRETED INTO THE RENAL TUBULE

Acids Bases

Penicillins Cephalosporins Salicylic acid Probenecid Thiazides Glucuronoconjugates

Morphine Quinine Quaternary compounds Catecholamines

RENAL CLEARANCE OF DRUGS

- Renal clearance refers to the volume of plasma from which the kidneyremoves the drug per unit time.

- Since the removed drug passes into urine, renal clearance can becalculated by:

d F x U

rCL = ))))))))

d P

where:F = urine flow rate

dU = Urine concentration of the drug

dP = Plasma concentration of the drug

-Renal clearance depends on the following renal factors:1) Glomerular filtration rate.2) Tubular fluid Ph.3) Extent of passive reabsorption of the drug.4) Extent of active tubular secretion of the drug.

r-CL of a drug can be used as a marker of the process of renal drugelimination. In fact:

ra) CL of 100-150 ml/min indicates glomerular filtration.

rb) CL > 150 ml/min indicates tubular secretion.

rc) CL < 100 ml/min indicates tubular reabsorption (or protein binding).


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BILIARY EXCRETION OF DRUGS

-Biliary excretion may play a major role in drug removal of three kinds ofcompounds:

1) anions.2) cations3) some nonionized molecules.

-These compounds are transported from the liver cell into the bilecanaliculus by three distinct active transport systems.

-The actively secreted drugs generally do not recycle (since they are toohighly charged to diffuse back across the intestinal epithelium) and areultimately eliminated with the feces.

-Drugs which are actively excreted may be highly concentrated into thebile (bile/plasma ratios of 20:1 are not exceptional)

-On the other hand, drugs excreted into the bile by passive diffusion orafter conjugation frequently undergo an enterohepatic cycle.


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Drug Elimination(Practice questions)

1) Which of the following pairs of properties are common to most drug metabolites?

A) Decreased water solubility, increased pharmacological activityB) Increased toxic potential, no pharmacological activity C) Decreased water solubility, decreased pharmacological activity D) Increased water solubility, no pharmacological activity E) Increased water solubility, increased toxic potential

2) Which of the following statements best defines the total clearance of a drug?

A) The fraction of drug reaching the systemic circulation after administration B) The fraction of drug removed from the plasma per unit time C) The volume of plasma from which the drug is removed per unit time D) The volume of plasma cleared by the kidney per unit timeE) The amount of drug removed from plasma per unit time F) The amount of drug biotransformed by the liver per unit time

3) An 83-year-old man recently diagnosed with prostatic hyperplasia, started a treatmentwith prazosin, one capsule daily. Prazosin has a total clearance of 12.6 L/h and a hepaticclearance of 11.4 L/h. Knowing that in an elderly person liver microsomal enzymes aredecreased, which of the following drug parameters was most likely increased in thispatient?

A) Hepatic clearanceB) First pass lossC) Volume of distributionD) Renal clearanceE) Half-life

4) A drug has a total clearance of 300 mL/min and 20% of the drug is eliminated as such bythe kidney. On the assumption that, in this case, only liver and kidney are involved in theelimination processes, which of the following will be the hepatic clearance of that drug (inmL/min)?

A) 30B) 60C) 120D) 180E) 240


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F) 300

5) The oral bioavailability of a new drug, studied in healthy volunteers, turned out to be 20%. Knowing that in this case all the administered drug reached the portal circulation, andthat the liver blood flow is about 1500 ml/min, which of the following will be the hepaticclearance the drug (in mL/min)?

A) 500B) 800C) 1200D) 1500E) 2000

6) A 55-year old woman with chronic obstructive pulmonary disease has been receivingtheophylline, a drug biotransformed by CYP1A2 isozyme. Few days ago the patient startedtaking erythromycin (a macrolide antibiotic) for an upper respiratory tract infection.Knowing that a pharmacokinetic interaction can occur between erythromycin andtheophylline, which of the following statements best explains the risk of overdose toxicityof these drugs? A) Theophylline: risk increasedB) Theophylline: risk unaffectedC) Theophylline: risk decreased D) Erythromycin: risk increasedE) Erythromycin: risk decreasedF) Erythromycin: risk much increased

7) A 61-year-old man suffering from epilepsy had been receiving carbamazepine, ananticonvulsant drug biotransformed by CYP3A4 isozyme. Few days ago the patient felt anannoying heartburn and started taking an over the counter preparation containingcimetidine, an inhibitor of most cytochrome P450 isozymes. Which of the following eventsmost likely occurred after few days of cimetidine therapy?

A) Plasma levels of carbamazepine were decreased B) Pharmacological effects of carbamazepine were reducedC) The therapeutic index of carbamazepine was increaseD) Plasma levels of cimetidine were decreasedE) The risk of overdose toxicity of carbamazepine was increased

8) A 63-year-old man underwent surgery because of a gastric carcinoma. He received an IM


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injection of lorazepam before the operation in order to allay the pain anticipatory anxiety.The drug is biotransformed by the most common phase II reaction of drugbiotransformation. Which of the following reactions is most likely involved?

A) HydrolysisB) Reduction C) GlucuronidationD) AcetylationE) Sulfate conjugationF) Methylation

9) Which of the following reactions of drug biotransformation can occur slowly in morethan 50% of Caucasians because of an inherited deficiency of the drug metabolizingenzyme?

A) HydrolysisB) AcetylationC) GlucuronidationD) ReductionE) MethylationF) Sulfation

10) Which of the following factors can affect the renal clearance of a drug?

A) Oral bioavailabilityB) PKaC) Route of administrationD) Administered dose E) Volume of distribution

11) The pharmacokinetics of a new drug was studied in a healty volunteer. It was found thatthe drug had a renal clearance of 55 mL/min when the pH of the urine was 8, and a renalclearance of 110 mL/min when pH of the urine was 5. Which of the following was mostlikely the chemical nature of that drug?

A) Weak baseB) Non ionizable C) Weak acidD) Strong base E) Strong acid


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12) A 52-year-old woman, suffering from renal insufficiency, developed pneumonia due toPseudomonas aeruginosa and a treatment with ceftazidime was planned. Ceftazidime iseliminated almost entirely by the kidney and its clearance in this patient was estimated tobe 25 mL/min (normal: 100 mL/min). Assuming that the standard therapeutic dose ofceftazidime is 1 g/daily, which of the following was most likely the initial dose (in g/die)given to the patient?

A) 0.05B) 0.10 C) 0.25D) 0.75E) 1.5F) 1.8

13) The pharmacokinetics of a new drug was studied in a young healthy volunteer. Thefollowing data were obtained:- Volume of distribution 347 L- Oral bioavailability: 10%- Metabolism by the liver 80%- Renal clearance 5 mL/min.

Which of the following statements best explains the reason for the low renal clearance ofthat drug ?

A) The drug is mainly eliminated by the liver B) The drug is extensively reabsorbed by the renal tubuleC) The drug is actively secreted by the renal tubuleD) The drug is filtered very slowly by the glomerulusE) The drug has a very low oral bioavailabilityF) The drug has a large volume of distribution

14) The elimination of a new drug was studied in a healthy volunteer. It was found that :- The drug was totally eliminated by the kidney.- The GFR was 140 mL/min.- About 50% of the drug was reabsorbed by the renal tubule.

Which of the following) was most likely the renal clearance of that drug (in mL/min) ?

A) 180B) 240 C) 60D) 82E) 70


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15) Which of the following factors can affect the renal clearance of a drug?

A) The administered dose B) The glomerular filtration rateC) The bioavailability of the drugD) The first pass loss of the drugE) The pH of the intestinal lumen F) The volume of distribution of the drug

Drug Elimination(Answers and explanations)

1) Learning objective: describe the main feature common to most drug metabolitesAnswer: DDrugs are generally foreign compounds (xenobiotics) and therefore are, as a rule, eliminated fromthe body in order to maintain homeostasis. Since many drugs are not water soluble,biotransformation is the way to turn drugs into more water soluble products that can be readilyeliminated by the kidney. Most drug metabolites have lost all pharmacological activity.A) Drug metabolites can have less water solubility than that of the parent compound, but this is avery rare case. Drug metabolites can have more pharmacological activity than that of the parentcompound, but again this is not common to most drug metabolites.B) Since overdose toxicity is mainly related to the pharmacological effect of the drug, metaboliteswith no pharmacological activity are devoid of toxic potential, in most cases. C, E) (see explanation above)

2) Learning objective: define the term “clearance of a drug”.Answer: CThe total clearance is defined as the volume of fluid (usually plasma) from which the drug isremoved per unit of time.D) this would be the definition of renal clearance.A, B, D, E) All these definitions refer to the amount of the drug. Clearance is not a measure of anamount but a measure of a volume.

3) Learning objective: explain why a decrease in liver microsomal enzymes can affect the halflife of a drug.Answer:.EThe hepatic clearance of prazosin indicates that almost all the drug is eliminated by hepaticbiotransformation. A decrease in microsomal enzymes will decrease the rate of drugbiotransformation, i.e. the hepatic clearance. Since the renal clearance is not affected (rememberthat renal and hepatic clearance are independent processes) the total clearance will bedecreased. .Remembering that t½ = 0.7 Vd / CL, the half-life of the drug will be increased.A, B) These parameters will be decreased, not increased.C) The volume of distribution of a drug is independent from drug elimination.


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E).(see explanation above)

4) Learning objective: calculate the liver clearance of a drug, given sufficient data.Answer: EThe total clearance of a drug is the sum of the clearances of various organs . If 20% of the drug iseliminated as such by the kidney the renal clearance will be 20% of the total clearance, i.e. 60mL/min. Since it has been assumed that only liver and kidney are involved in the eliminationprocesses, the hepatic clearance will 300-60 = 240 mL/min.A, B, C, D) (see explanation above)

5) Learning objective: calculate the hepatic clearance of a drug, given sufficient dataAnswer CBy definition clearance is the volume of blood from which all the drug is removed per unit time. Ifall the drug were removed by the liver, the liver clearance would equate the liver blood flow(volume per unit time), i.e 1500 mL/min. Since 20% of the drug can reach the general circulation itfollows that 80% of the drug is removed by the liver, that is the drug contained in 80% of the bloodflow. Therefore the liver clearance will be 80% of the liver blood flow.A, B, D, E) (see explanation above)

6) Learning objective: explain the consequences of drug induction or inhibition of microsomalenzymes.Answer: AMacrolide antibiotics like erythromycin have been reported to inhibit the cytochrome P450-mediated metabolism of several drugs, including theophylline. Drugs that inhibit microsomalenzymes may increase the toxicity of other drugs that are metabolized by those enzymes sincethe elimination of those drugs is decreased. This is especially important in case of theophylline, adrug with a narrow therapeutic index.B, C, D, E, F) (see explanation above)

7) Learning objective: explain the main consequences of drug induction or inhibition ofmicrosomal enzymes Answer: EDrugs that inhibit microsomal enzymes may increase the toxicity of other drugs that aremetabolized by those enzymes since the elimination of those drugs is decreased. Cimetidine caninhibit most cytochrome P450 enzymes, including CYP3A4 isozyme and can therefore increasethe risk of carbamazepine overdose toxicity.A, B) If the elimination of a drug is decreased, its plasma levels and pharmacological effectsshould increase, not decrease.C) The therapeutic index of a drug is the ratio between the toxic dose and the effective dose. Bydecreasing the elimination of the drug the therapeutic index will decrease, not increase.D) If a drug inhibits most cytochrome P450 enzymes, plasma levels of this drug should increase,


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not decrease, after few days of therapy.

8) Learning objective: describe the main features of glucuronic acid conjugation.Answer:.CGlucuronidation is the most common conjugation reaction of xenobiotics. Glucuronic acid (aproduct of carbohydrate metabolism) can be conjugated with many compounds of the general

2type R-OH, R-COOH, R-NH , R-SH. Glucuronidation occurs mainly in the liver and is catalyzed bya microsomal enzyme named UDP-glucuronosyltransferase.A, B, D, E, F) (see explanation above)

9) Learning objective: describe the most important factors affecting drug biotransformation.Answer: BAcetylation is catalyzed by N-acetyltransferase, an enzyme which is under genetic control. Aboutone half of people of Caucasian origin are slow acetylators, since they have a deficiency of theenzyme, inherited as an autosomal recessive trait. A, C, D, E, F) (see explanation above)

10) Learning objective: explain the relationship between the pKa of a drug and its renalclearance.Answer: BThe pKa of a drug determines the lipid/water solubility of that drug in relation to the pH of thesolution. Since water soluble drugs cannot be reabsorbed by the kidney tubule, renal excretion ofthat drug will be influenced by the pKa, that is clearance will be affected.A, C) These properties are related to drug absorption, which has nothing to do with drugelimination measured by renal clearance.D) The clearance of a drug, which follows a first order kinetics, is independent from theadministered dose.E) The distribution of a drug has nothing to do with drug elimination.

11) Learning objective: explain how a change in urine pH can change the renal clearance of adrug.Answer: AA weak base is more ionized, i.e. more water soluble, in an acidic medium. Since only lipidsoluble drugs can cross tubular cell membrane by lipid diffusion, that drug will be less reabsorbedby the tubule and therefore its renal clearance will be increased.B, C, D, E) (see explanation above)

12) Learning objective: calculate the initial therapeutic dose for a patient, given sufficient data.Answer: CIf the drug is cleared almost entirely by the kidney and its clearance is reduced to one fourth of


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normal, the dose should also be reduced to one fourth of normal.A, B, D, E, F) (see explanation above)

13) Learning objective: explain the reasons of a low renal clearance of a drug.Answer: BIn a healthy person (i.e. a person with a normal GFR) the only reason why the renal clearance ofa drug is low is because the drug is extensively reabsorbed by the renal tubule.A) Yes the drug is mainly eliminated by the liver but this is not the reason of a low renalclearance, since there is no information about the total clearance.C) In this case the renal clearance of the drug should be high.D) The GFR is normal in a young healthy person.E, F) Bioavailability and volume of distribution have nothing to do with renal clearance.

14) Learning objective: calculate the renal clearance of a drug, given sufficient data.Answer: EIf one half of the drug was reabsorbed by the renal tubule the renal clearance of the drug will beone half of the GFR, i.e. 70 mL/min.A, B, C, D) (see explanation above)

15) Learning objective:: explain how glomerular filtration rate can affect the renal clearance of adrug.Answer: BBy definition the renal clearance of a drug is the volume of plasma from which the kidney removesthe drug per unit time. Glomerular filtration rate is the volume of plasma filtered by the kidney perunit time. If this volume is increased or decreased, also the drug dissolved in that volume will deincreased or decreased, i.e. its clearance will be affected.A, C, D, E, F) (see explanation above)

DRUG ELIMINATIONAnswer key

1) D2) C3) E4) E5) C

6) A7) E8) C9) B

10) B

11) A12) C13) B14) E15) B

babbini fm03 fm03x drug elimination 14 sum

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