Drug elimination (metabolism,

excretion) Anton Kohút

DRUG METABOLISM

major site of drug metabolism – liver, exceptions:- suxamethonium and procaine - plasma cholinesterase

- tyramine - intestinal wall

Phase 1Phase 1- - lipophilic molecules are converted lipophilic molecules are converted

into more polar molecules into more polar molecules Reactions are catalyzed by the Reactions are catalyzed by the cytochrome P-450 (CYP) cytochrome P-450 (CYP)

by: by: oxidation oxidation reductionreduction hydrolysishydrolysis- p- products are often less eactive roducts are often less eactive

than the parent compoundsthan the parent compounds- after metabolism may be - after metabolism may be

excreted by kidneysexcreted by kidneys- each of the enzyme has a low - each of the enzyme has a low

specificityspecificity

Phase 2Phase 2 consists of conjugation consists of conjugation

reactionsreactions Most often involved groups in Most often involved groups in

conjugation are:conjugation are: glucuronylglucuronyl sulphatesulphate methylmethyl acetylacetyl glycylglycyl glutamylglutamyl

The two phases of drug metabolism

Metabolism of imipramine

Involvement of some isoform of CYP in the metabolism

FACTORS INFLUENCING DRUG

METABOLISM - systemic pathological processes - liver - systemic pathological processes - liver

diseases, heart failurediseases, heart failure - age- age - sex- sex - body temperature- body temperature - genetic factors - - genetic factors - polymorhismpolymorhism - drug interactions- drug interactions enzyme inhibition, enzyme inhibition,

enzyme induction enzyme induction

Drug interactions - enzyme induction

Drug inductionDrug induction increase of enzyme activity increase of enzyme activity

can decrease drug potency,can decrease drug potency,- result is an increased synthesis - result is an increased synthesis

of microsomal enzymes after of microsomal enzymes after repeated use of drugs repeated use of drugs

- generally, metabolism of - generally, metabolism of inducers itself is increased as inducers itself is increased as well as various other well as various other compounds, compounds,

- increase of metabolism may - increase of metabolism may increase toxicity of increase toxicity of paracetamol – toxic paracetamol – toxic metabolitesmetabolites

Drugs that cause Drugs that cause inductioninduction

barbiturates, barbiturates, carbamazepine, ethanol carbamazepine, ethanol (chronic use), (chronic use), glutethimide, glutethimide, griseofulvin, griseofulvin, meprobamate, meprobamate, phenytoin, phenytoin,

rifampicin, rifampicin, sulphinpyrazone, sulphinpyrazone,

Drug interactions - enzyme inhibition

Drug inhibitionDrug inhibition - enzyme inhibition - enzyme inhibition

can slow down the can slow down the metabolismmetabolism

- action of - action of coadministrated drug coadministrated drug may be increased and may be increased and prolonged prolonged

Drugs that cause Drugs that cause inhibitioninhibition

- cimetidine,- cimetidine, - erythromycin,- erythromycin, - quinolone - quinolone - sodium valproat,- sodium valproat, - allopurinol- allopurinol

Genetic polymorphism

Genetic polymorphism

Genetic polymorphism

1. Plymorphism in 1. Plymorphism in acetylation acetylation (rapid or slow (rapid or slow acetylatorsacetylators – isoniasid (INH), hydralazine and – isoniasid (INH), hydralazine and procainamide, sulphasalazineprocainamide, sulphasalazine

2. 2. Poor oxidisersPoor oxidisers – debrisoquine, metoprolol, timolol, – debrisoquine, metoprolol, timolol, haloperidolhaloperidol

3. Glucose-6-phosphate dehydrogenase 3. Glucose-6-phosphate dehydrogenase deficiency deficiency G-6-PDG-6-PD – risk of haemolysis – aspirin, probenecid, – risk of haemolysis – aspirin, probenecid,

quinine, chloroquine, nitrofurantoin, some quinine, chloroquine, nitrofurantoin, some sulphonamidessulphonamides

4. 4. Pseudocholinesterase deficiencyPseudocholinesterase deficiency – malignant – malignant hyperthermia – suxametonium, hyperthermia – suxametonium,

CYP 2D6

Drug excretionDrug excretion

- Drugs are exreted : either unchanged or as metabolites. - Lipid-soluble drugs are not readily eliminated until they are metabolized to more polar compounds

Drug excretionDrug excretion

Renal excretionExtrarenal excretion

Renal excretion 1. Glomerular filtration - passive1. Glomerular filtration - passiveDepends Depends on: fractional plasma protein bindingon: fractional plasma protein binding glomerular filtration rate (size of molecules)glomerular filtration rate (size of molecules) ((MW 68 000) is completely held back MW 68 000) is completely held back by this way is removed about 20% of drugs from the bloodby this way is removed about 20% of drugs from the blood

2. Passive tubular reabsorption2. Passive tubular reabsorption the the nonionized formsnonionized forms of weak acids and bases undergo of weak acids and bases undergo

passive reabsorption. passive reabsorption. The The concentration gradientconcentration gradient for back-diffusion is created by for back-diffusion is created by

the reabsorption of water with Na+ and other inorganic ions. the reabsorption of water with Na+ and other inorganic ions.

When the tubular urine is made When the tubular urine is made more acidicmore acidic, the , the excretion of weak acids is reduced (alkalinization excretion of weak acids is reduced (alkalinization of the urine have the opposite effects on the of the urine have the opposite effects on the excretion of weak bases). excretion of weak bases).

Treatment of drug poisoning,Treatment of drug poisoning, the excretion of the excretion of some drugs can be hastened by appropriate some drugs can be hastened by appropriate alkalinization or acidification of the urine. alkalinization or acidification of the urine.

Renal excretion (cont.)3. Active tubular secretion3. Active tubular secretion Many Many organic acidsorganic acids (such as penicillin) and metabolites (such as penicillin) and metabolites

(such as glucuronides) are transported by the system that (such as glucuronides) are transported by the system that secretes naturally occurring substances (such as uric acid). secretes naturally occurring substances (such as uric acid).

Organic bases,Organic bases, such as tetraethylammonium, are such as tetraethylammonium, are

transported by a separate system that secretes choline, transported by a separate system that secretes choline, histamine, and other endogenous bases. histamine, and other endogenous bases.

The The carrier systems are relatively nonselective,carrier systems are relatively nonselective, and and

organic ions of similar charge compete for transport. organic ions of similar charge compete for transport. Both transport systems also Both transport systems also can be bidirectionalcan be bidirectional, and at , and at

least some drugs are both secreted and actively least some drugs are both secreted and actively reabsorbed. (an endogenous organic acid is uric acid).reabsorbed. (an endogenous organic acid is uric acid).

Excretion by other routes

Biliary and fecal excretionBiliary and fecal excretion Saliva, sSaliva, sweat, tearsweat, tears - t - the concentration of he concentration of

some drugs in saliva parallels that in some drugs in saliva parallels that in plasma.plasma.

Breast milkBreast milk - e - excretion by breast milk is xcretion by breast milk is dependent mainly upon diffusiondependent mainly upon diffusion, , Milk is Milk is more acidic than plasma, basic compounds more acidic than plasma, basic compounds may be slightly concentrated in this fluidmay be slightly concentrated in this fluid..

Excretion by Other Routes

1. Saliva1. Saliva Excretion of drugs into sweat, saliva, and tears is Excretion of drugs into sweat, saliva, and tears is

quantitatively unimportant.quantitatively unimportant. Excretion by saliva is dependent mainly upon diffusion Excretion by saliva is dependent mainly upon diffusion Drugs excreted in the saliva enter the mouth, where they Drugs excreted in the saliva enter the mouth, where they

are usually swallowed. are usually swallowed. The concentration of some drugs in saliva parallels that in The concentration of some drugs in saliva parallels that in

plasma. plasma. Saliva may therefore be a useful biological fluid in which Saliva may therefore be a useful biological fluid in which

to determine drug concentrations when it is difficult or to determine drug concentrations when it is difficult or inconvenient to obtain blood. inconvenient to obtain blood.

2. Breast milk2. Breast milk Excretion by breast milk is dependent mainly Excretion by breast milk is dependent mainly

upon diffusionupon diffusion Milk is more acidic than plasma, basic compounds Milk is more acidic than plasma, basic compounds

may be slightly concentrated in this fluid, may be slightly concentrated in this fluid, Nonelectrolytes, such as Nonelectrolytes, such as ethanol and ureaethanol and urea, ,

readily enter breast milk and reach the same readily enter breast milk and reach the same concentration as in plasma, independent of the pH concentration as in plasma, independent of the pH of the milk.of the milk.

Excretion of drugs in breast milk are potential Excretion of drugs in breast milk are potential sources of unwanted pharmacological effects in sources of unwanted pharmacological effects in the nursing infant.the nursing infant.

3. Feces3. Feces Substances excreted in the feces are mainly Substances excreted in the feces are mainly

unabsorbed orally ingested drugs or unabsorbed orally ingested drugs or metabolites excreted in the bile and not metabolites excreted in the bile and not reabsorbed from the intestinal tract. reabsorbed from the intestinal tract.

4. Biliary excretion4. Biliary excretion

Elimination

Rate of elimination Rate of elimination Elimination of most drugs from the body after therapeutically relevant doses follows first-order kinetics.To illustrate first order kinetics we might consider what would happen if we were to give a drug by i.v. bolus injection, collect blood samples at various times and measure the plasma concentrations of the drug. We might see a decrease in concentration as the drug is eliminated.

First-order kinetics Elimination half-life (t1/2) First-order kinetics Elimination half-life (t1/2)

Definition: Elimination half-life is the time it takes the drug concentration in the blood to decline to one half of its initial value.

It is a secondary parameter : The elimination half-life is dependent on the ratio of VD and CL.

Unit : time (min, h, day)

First order kinetics half - life

Most drugs exhibit first order kinetics – disappeaance Most drugs exhibit first order kinetics – disappeaance of drug from plasma follows exponential patterns. of drug from plasma follows exponential patterns.

The rate of elimination is directly proportional to The rate of elimination is directly proportional to drug concentration.drug concentration.

Plasma half-life is directly proportional to the volume Plasma half-life is directly proportional to the volume of distribution and inversely proportional to the overall of distribution and inversely proportional to the overall rate of clearancerate of clearance

With repeated dosage or sustained delivery of a drug With repeated dosage or sustained delivery of a drug the plasma concentration approaches a steady state the plasma concentration approaches a steady state within 4-5 half-lifes.within 4-5 half-lifes.

Rate of eliminationRate of eliminationElimination which follows first-order kinetics:

dC/dt = - kel . C

kel …. rate constant of elimination rate of change is proportional to concentration and is therefore decreasing with time as the conc. decreases

0

2.5

5

7.5

10

0 2 4 6 8 10

time (h)

Con

c. (m

g/L)

5

2.5

1.250.625

Dose=100 mg, Vd=10 L,

C0=Dose/Vd = 10 mg/L

Rate of eliminationRate of elimination

half-life : t1/2

C= C0 / 2

t= t1/2 = ln2 / kel = 0.693/ kel

after 4 half-lives:

6% remaining, 94% eliminated

0

2.5

5

7.5

10

0 2 4 6 8 10

time (h)

Con

c. (m

g/L)

5

2.5

1.250.625

Dose=100 mg, Vd=10 L,

C0=Dose/Vd = 10 mg/L

monoexponential decay: C(t) = C0 . e- kel . t

Saturation kinetics

In a few cases as In a few cases as ethanol, ethanol, phynytoin and salicylatephynytoin and salicylate disapppearance of drug disapppearance of drug from plasma does not from plasma does not follow exponential follow exponential patterns.patterns.

Pattern of desappearance Pattern of desappearance of drug is linear – drug is of drug is linear – drug is removed at a constant rate removed at a constant rate that is indipendent of that is indipendent of plasma concentration plasma concentration

This is often called This is often called zero zero order kineticsorder kinetics

Use of t1/2:

1/ t1/2 can be used to predict how long it will take for the drug to be eliminated from plasma.

0

2.5

5

7.5

10

0 2 4 6 8 10

time (h)

Con

c. (m

g/L

)

5

2.5

1.250.625

t1/2 = 2 hours

1. 2.

3. 4.

percent eliminated

5.

50 75 87.5 94 97%