Pharmacokinetics

pharmakon - drug
kinetikos - To do with movement of drug Drug effect. pharmacokinetics determines the

onset, duration, and intensity of a drug's

The quantitative temporal determination of the fate of substances administered externally to a living organism OR The study of the mechanisms of absorption and distribution of an administered drug, the rate at which a drug action begins and the duration of the effect, the chemical changes of the substance in the body and the effects and routes of excretion of the

metabolites of the drug.

Drug Passage across the cell membrane determines ADME

Biological Membrane

Plasma

membrane

Proteins,

lipids

and

carbohydrates

Bimolecular

Lipid

bilayer

Passage

of

molecules porous in nature Also has inter cellular gaps 100 Ao thick Having hydrophilic (polar head) and

hydrophobic (non-polar tail ) end.

Polar

group-

glycerol or

phosphate+ hydroxyl

ethanol of

amine/

choline

group

cholesterol)- projected out side of the surface

Hydrocarbon chain embedded in the matrix

Absorption
Concerns the processes of entry of a drug into the systemic circulation from the site of its administration.

The

determinants

of

absorption

are

Solubility, Concentration gradient, Surface area and vascularity

Mechanism of

absorption: Drug are absorbed

through the membrane either by

Filtration
Passive diffusion Carrier transport

Passive diffusion Filtration through lipid

Carrier transport

 Filtration is passage of a drug (MW < 100-150)

through aqueous pores in the membrane (epithelial,

endothelial) The driving force is Drug concentration gradient

(Ficks law)
Lipid insoluble drugs cross the biomembrane by filtration only if their molecular size is smaller than

the diameter of the enlarged aqueous pores.

The filtration has an importance mainly at the level of renal glomerulus, where the size of capillaries have large pores (40 ) and most drugs (even albumin) can filtrate. The brain capillary pores have small size.

Passive diffusion

Movement

of

drugs

through

membrane

towards

concentration gradient. Membrane play no role

This is the most important mechanism of drug

absorption. Lipid soluble drugs are diffused by dissolving in the lipoidal matrix of the membrane, rate of diffusion is proportional to the ratio of lipid water partition

coefficient.
More lipid soluble drug diffused higher in

concentration.

Ionizaiton and Diffusion - Drug absorption are influenced by pH and the drug pKa Ionization state of the drug is an important factor: charged drugs diffuse-through lipid

environments with difficulty.

Most of the drugs are weak electrolyte and

their ionization is pH dependent; However,

strong electrolyte are completely dissociates.

 A weak acid at acid pH will be more lipidsoluble because it is uncharged and

uncharged

molecules

move

more

readily

through a lipid (nonpolar) environment, like the some membrane, than charged molecules Similarly a weak base at alkaline pH will be

more lipid-soluble because at alkaline pH a

proton will dissociate from molecule leaving it uncharged and again free to move through

lipid membrane structures

For drug absorption

Acidic drugs absorb in Acidic media

Basic drugs absorb in basic media

 Uncharged form: lipid-soluble charged form: aqueous-soluble, (does not pass relatively biological

lipid-insoluble

membranes easily) Lipid diffusion depends on adequate lipid solubility

Drug ionization reduces a drug's ability to

cross a lipid bilayer.

 Acidic drug e.g Aspirin remain unionized at acidic

pH of stomach and absorbed from the stomach while base are largely absorbed from area;

intestine.
Acidic drug which absorbed from the stomach to the gastric mucosal cell, revert to ionized form

within the cell (PH=7)and only slowly passes to

the extra cellular fluids Acidic drug ionized more in alkaline urine- thus restricted to diffuse back to the plasma and enhance the process of elimination

Active transport (For larger molecules drugs)

By combination with a carrier molecule which

acts as a ferry-boat across the lipid region of the membrane. Carrier transport is saturable and competitively inhibited by analogues which utilize the same

carrier.
Active transport is a movement against the concentration gradient. It needs energy and is

inhibited by metabolic poisons. Levodopa and

methyldopa are actively absorbed from the gut by aromatic amino acid transport.

Facilitated diffusion This proceeds more rapidly than passive (simple) diffusion and translocates even nondiffusible substrates, but along their concentration gradient, therefore, does not need energy. Example: Facilitated transport of glucose.

a. Carrier mediated

Drug +carrier = complex; then translocates.

Polar

molecules

(Hydrophilic)

coated

with

hydrophobic layer thus facilitate transport. Ionophores: lipid coat on a polar core

b. Pinocytosis

Carrier mediated
Active Facilitated transportdiffusion
Active transport: Moves against concentration gradient Need energy and can be block by metabolic poisons a drug that harms us and cant be absorbed. Selective accumulation occur only intracellular drug Natural metabolites are actively absorbed modified drugs may not be absorbed.

Pinocytosis involves the invagination of a part of the cell membrane and trapping within the

cell of a small vesicle containing extracellular

constituents. The vesicle contents can than be released within the cell, or extruded from the other side of the cell. Pinocytosis is important for the transport of some macromolecules

(Iron vitamin B12).

Absorption It is the passage of drug from the site of administration into the circulation.

Aqueous solubility. Drugs given in solid form

must dissolve in the aqueous biophase before they are absorbed. For poorly water soluble drugs (aspirin, griseofulvin) the rate of dissolution governs the rate of absorption. If a

drug is given as water solution, it is absorbed

faster than the same given in solid form or as a oily solution.

 Concentration. Passive transport depends on the concentration gradient. A drug given as concentrated solution is absorbed faster than dilute solution. Area of absorbing surface. If the area is

larger, the absorption is faster.

Vascularity absorption gradient of and absorbing maintains the surface. Blood circulation removes the drug from the site of concentration Increased across membrane.

blood flow hastens drug absorption.

Route

of

administration

affects

drug

absorption, because each route has its own peculiarities.

Effect of absorption: a. Oral route

route of administration on drug

b. Subcutaneous route or intramuscular route c. Topical route

Oral application. Unionized lipid soluble drugs (e.g. ethanol) are readily absorbed from GIT. Acid drugs (aspirin, barbiturates, etc.) are

predominantly unionized in the acid gastric

juice and are absorbed from the stomach. Acid drugs absorption from the stomach is slower,

because the mucosa is thick, covered with

mucus and the surface is small. Basic drugs (e.g. atropine, and morphine, absorbed etc.) only are largely the ionized are from

duodenum.

Presence of food dilutes the drug and retards

absorption. Certain drugs form poorly absorbed complexes with food constituents, e.g. tetracyclines with

calcium present in milk.

Food delays gastric emptying. Most drugs are absorbed better if taken on an empty stomach.

Highly ionized drugs, e.g. amikacin, gentamicin,

neostigmine, are poorly absorbed when given orally.

Certain drugs are degraded in the GIT, e.g. penicillin G by acid, insulin by peptidases, and are ineffective orally.

Enteric coated tablets (having acid resistant

coating) and sustained released preparations can be used to overcome acid ability, gastric irritancy

and brief duration of action.

b. Even acidic drug absorption from gut is less due to

Thick mucus membrane

Small surface area Slow dissolution c. Presence of Dilution of drugs food: Interfere absorption by

d.

Certain

drugs

degrade

by

the

acidic

environment of stomach e.g. Pen-G, Insulin,

Cephalosporin etc. Remedy: Enteric coating or surface coating or other sustained release product free from such draw back.

Subcutaneous Drug deposited directly into the vicinity of the capillaries. Lipid soluble drug directly passes across the whole surface of the capillary membrane. Capillaries are highly porous - do not obstruct

ionized molecules, even large molecules are absorbed

through lymphatic system. Drug those can not absorbed through oral route can absorbed through IM or SC

 Sub

cutaneous

absorption

is

slower

then

Intra

muscular But both are faster than oral route. Massage absorption Addition of or application of heat accelerate the

Vasoconstrictor- adrenaline
Hydrolase- hyaluronidase

Depot preparation oily solution.

Topical site: Depending on the lipid solubility of the drugs. Only few drugs can penetrate through the intact

skin, e.g. nitroglycerin, hyoscine, estradiol.

Corticosteroid- applied over skin can have systemic

effect and pituitary adrenal suppression.

Absorption can be promoted by rubbing the skin, also incorporation of smoothening agent or vasodialating agent enhance absorption. Abrasive surface accelerate the absorption

process.

Intestinal absorption:

- duodenum (B1, Fe2+)

- ileum (B12, A, D, E, K) - large intestine (water, Na+, Cl-, K+)

With oral administration, drugs are absorbed into the portal circulation and initially distributed to the liver. Drugs administered I.V enters directly into the Systemic circulation. But drugs administered PO are 1stexposed to liver through portal circulation and may be

extensively metabolized before reaching the

rest of the body (syst. circulation). For some drugs, their rapid hepatic metabolism decreases bio-availability the First-Pass effect. Example: Propranolol, Lidocaine.

Avoiding the first-pass effect

sublingual (e.g. nitroglycerin) direct access

to systemic circulation transdermal use of suppositories in the lower rectum {if suppositories move upward, absorption may

occur through the superior hemorrhoidal

veins, which lead to the liver} inhalation: first-pass pulmonary loss by excretion or metabolism may occur.

Bioavailability: Is defined as the fraction of unchanged drug

reaching

the

systemic

circulation

following

administration by any route Bioequivalence: For Bioequivalence to occur between two formulations of the same compound, they must have the same bioavailability and the same rate of absorption. Bioequivalence is a term used

when comparing brand name and generic drugs

 Bioavailability refers to the rate and extent of absorption of a drug from dosage form as

determined by its concentration-time curve

in blood or by its excretion in urine.

It is a measure of the fraction (F) of

administered dose of a drug that reaches the systemic circulation in the unchanged form.

 Bioavailability of a drug injected i.v. is

100%, but is frequently lower after oral ingestion, because: The drug may incompletely absorbed The absorbed drug may undergo first

pass

metabolism

in

intestinal

wall

and/or liver, or be excreted in bile.

Plasma concentration (mcg/ml)

Determination of Bioavailabilty
AUC area under the curve F bioavailability
AUC p.o. F = ------------ x 100% AUC i.v.

(i.v. application)
(p.o. application)

Time (h)

10

15

Plasma concentration time curves of the three preparations of a drug which contain the same amount. Formulation B is more slowly absorbed than A and may not produce therapeutic effect. Formulation C is absorbed to a lesser extent (it has lower bioavailability).

Distribution
It is the passage of a drug from the circulation to the tissue and the site of its action. Volume of distribution (Vd) is the ratio

between the amount of drug in body (dose given) and the concentration of the drug (C) measured in blood or plasma. Vd = (amount of drug in body)/C where C is the concentration of drug in blood or plasma.

The extent of distribution of a drug depends on its lipid solubility, ionization at physiological pH (dependent on pK), extent of binding to plasma and tissue proteins, and differences in regional blood flow, disease like CHF, uremia,

cirrhosis.
Movement of a drug proceeds until an

equilibration is established between unbound drug in plasma and tissue fluids.

Body fluid compartments The total body water as a percentage of body mass varies from 50% to 70%, being rather less

in women than in man. Body water is distributed

into the following main compartments:

1. plasma (5% of body mass)

2. intestinal fluid (16%) 3. intracellular fluid (35%) 4. transcellular fluid (2%) 5. fat (20%)

Apparent volume of distribution (Vd)

It is accept that the body behaves as a single

homogeneous compartment with volume (Vd) in which the drug gets immediately distributed: Dose administered Vd = ----------------------------Plasma concentration

Two-compartment pharmacokinetic model (Biphasic model)

Drugs extensively bound to plasma proteins are

largely restricted to the vascular compartment

and have low Vd (e.g. warfarin 99% bound and its Vd is 0,1 L/kg). Drugs sequestrated in other tissues may have Vd much more than the total body water or even

body mass, e.g. digoxin (6 L/kg) and propranolol

(3 to 4 L/kg) because most of the drug is present in other tissues, and the plasma concentration is

low.
Therefore, in case of poisoning, drugs with large Vd are not easily removed by haemodialysis.

Redistribution Highly lipid soluble drugs given i.v. or by

inhalation get distributed to organs with high

blood flow (brain, heart, kidney, liver). Later they get distributed to less vascular tissues

(muscles

and

fat)

and

the

drug-plasma

concentrations falls.

The greater lipid solubility of the drug hastens its redistribution. Anaesthetic action of

thiopentone (thiopental) is terminated in few

minutes due to redistribution. However, when the same drug over is given repeatedly the or low continuously long periods

perfusion high capacity sites get progressively

filled up and the drug becomes longer acting.

Blood brain barrier (BBB): includes the capillary endothelial cells (which have tight junctions and lack large intracellular pores) and an investment of glial tissue, over the capillaries. A similar barrier is loctated in the choroid plexus.

BBB is lipoidal and limits the entry of non-lipid

soluble

drugs

(amikacin,

gentamicin,

neostigmine etc.). Only lipid soluble unionized drugs penetrate and have action on the CNS.

Efflux carriers like P-gp (glycoprotein) present

in brain capillary endothelial cells (also in intestinal mucosal, renal tubular, hepatic

canicular,
processes.

placental,

and

testicular

cells)

extrude drugs that enter the brain by other

Inflammation of the meninges of the brain

increases permeability of the BBB.

Dopamine (DA) does not enter the brain, but its precursor levodopa does. This is used later in parkinsonism.

GIT
L-DOPA (Levodopa)

Blood and peripheral tissues

Brain

13%
DDC DDC

COMT

70%

2729%

DDC DOPA-decarboxilase; COMT catechol-methyltransferase

Placental barrier Placental membranes are lipoidal and allow free

passage
to limit

of

lipophilic
foetal

drug,

while
to

restricting
maternally

hydrophilic drugs. The placental P-gp also serves exposure administered drugs.

However restricted amounts of nonlipid soluble drugs, when present in high concentration or for

long periods in maternal circulation, gain access

to the foetus. Thus, it is an incomplete barrier and many drugs, taken by the mother, can affect

the foetus or the newborn.

Penicillins, azithromycin, and erythromycin do not affect the foetus and can be used during the pregnancy.

Plasma protein binding (PPB)

Most drugs possess physicochemical affinity for plasma proteins. Acidic drugs bind to plasma albumin and basic drugs to 1 the

glycoprotein. Extent of binding depends on the

individual compound. Increasing concentration of a drug can progressively saturate the binding sites.

The clinical significant implications of PPB are:

a) Highly PPB drugs are largely restricted to the vascular lower Vd. b) The PPB fraction is not available for action. c) There is an equilibration between the PPB fraction of the drug and the free molecules of the drug. compartment and tend to have

d) The drugs with high physicochemical affinity for plasma proteins (e.g. aspirin, sulfonamides, chloramphenicol) can replace the other drugs (e.g. acenocoumarol, warfarin) or endogenous compounds (bilirubin) with lower affinity.

e) High degree of protein binding makes the drug

long acting, because bound fraction is not available for metabolism, unless it is actively excreted by the liver or kidney tubules.

f) Generally expressed plasma concentrations of the drug refer to bound as well as free drug. g) In hypoalbuminemia, binding may be reduced and high concentration of free drug may be

attained (e.g. phenytoin).

Tissue storage

Drugs may also accumulate in specific organs

or get bound to specific tissue constituents, e.g.: Heart and skeletal muscles digoxin (to muscle proteins) Liver chloroquine, tetracyclines, digoxin Kidney digoxin, chloroquine Thyroid gland iodine

 Brain

chlorpromazine,

isoniazid,

acetazolamide Retina chloroquine (to nucleoproteins) Iris ephedrine, atropine (to melanin)

Bones and teeth tetracyclines, heavy metals

(to mucopolysaccharide of connective tissue) Adipose tissues thiopental, ether,

minocycline, DDT

Metabolism (Biotransformation)
Includes chemical alteration of the drugs in the body. Most hydrophilic drugs (amikacin,

gentamycin, neostigmine, mannitol) are not

biotransformated unchanged. The mechanism to metabolize drugs is developed to protect the body from toxins. and are excreted

The primary site for drug metabolism is the

liver, other sites are the kidney, intestine, lungs, and plasma.

Metabolism of drugs may lead to the following:

a) Inactivation. Most drugs and their active

metabolites are converted to less active or

inactive metabolites, e.g. phenobarbital, morphine, propranolol, etc.

b) Active metabolite from an active drug

Many drugs are converted to one or more ctive metabolites (e.g. diazepam, amitriptyline). c) Activation of inactive drug. Few drugs (so called active prodrugs) are inactive as such. They metabolites (e.g. levodopa, need conversion in the body to one or more

benfothiamine, enalapril, perindopril).

The prodrug may offer advantages: their active

forms may be more stable; they can have

better bioavailability (e.g. benfothiamine), or other desirable pharmacokinetic properties or less side effects and toxicity.

Biotransformation reactions can be classified into two phases:

Phase I (no synthetic)

Phase II (synthetic, conjugation).

Phase I (no synthetic reactions)

Following phase I reactions, the metabolites are typically more polar (hydrophilic) which increases the likelihood of their excretion by the kidney. Phase I metabolic products may be

further metabolized
a) Oxidation is the most important Various drug metabolizing reaction. oxidation

reactions are hydroxylation; oxygenation at C-, N- or S-atoms; N or 0-dealkylation, oxidative deamination, etc.

Oxidative reactions are

mostly carried out

by a group of monooxygenases in the liver,

which in the final step involve cytochrome

P450 reductase and O2. There are more than 200 cytochrome P450 isoenzymes, differing in their affinity They for various substances into > 20 (drugs). are grouped

families.

CYP 3A4/5 carry out biotransformation of the largest number ( 50%) of drugs. In addition to the liver, these isoforms are expressed in the intestine (responsible for first pass metabolism at this site) and the kidney too.

Substrates:
Cumarins Mephenytoin Omeprazole

Tolbutamide Warfarin Phenytoin

Midazolam Nifedipine Erythromycin Cyclosporine

Caffeine Theophylline Tacrine

Chlorzoxazone

Dextrometorphan Debrisoquine

CYP2B6

CYP2A6 <5%

CYP2C19 <5%

CYP2C8/9/18 ~20%

CYP3A4/5 (3050%)

CYP1A2 ~15%

CYP2E1 ~10%

CYP2D6 <5%

CYP1A1

Inhibitors:
Methoxsalen Fluconazole Sulphaphenazole Ketoconazole Gestodene Furafylline Fluvoxamine Tetrahydro- Quinidine furane

Inducers:
Phenobarbital Phenobarbital Phenobarbital Rifampicin Rifampicin Phenobarbital Rifampicin Dexamethasone Carbamazepine Omeprazole Nicotine Ethanol Isoniazid

Barbiturates, streroids, theophyllin oxydaized oxidized enzymes. by by

phenothiazines, phenytoin, and many CYP450. other Some or

paracetamol, drugs other are drugs

benzodiazepines,

(adrenaline, mercaptopurine) and ethanol are

mitochondrial cytoplasmic

b) Reduction. This reaction is conversed of

oxidation and involves CYP450 enzymes working in the opposite direction. Drugs, primarily reduced, are

chloramphenicol, levodopa, halothane.

Levodopa (DOPA)

DOPA-decarboxylase Dopamine

c) Hydrolysis. This is cleavage of a drug molecule

by taking up a molecule of water.

Esterase Ester + H20 Similarly amides Acid + Alcohol and polypeptides are

hydrolyzed
Hydrolysis

by
occurs

amidase
in the

and
liver,

peptidases.
intestines,

plasma, and other tissues. Examples are choline

esters, procaine, lidocaine, pethidine, oxytocin.

d) Cyclization is formation of a ring structure from a straight chain compound, e.g. proguanil. e) Decyclization is opening up of a ring

structure of the cyclic molecule, e.g. phenytoin,

barbiturates.

Phase II synthetic (conjugation) reactions

These involve conjugation of the drug or its

phase

metabolite

with

an

endogenous

substrate to form a polar highly ionized organic acid, which is easily excreted in urine or bile. Conjugation reactions have high energy

requirements.

(1)Glucoronide important

conjugation

is

the

most

synthetic

reaction.

Compounds

with a hydroxyl or carboxylic acid group are

easily conjugated with glucuronic acid, which

is derived from glucose, e.g. chloramphenicol, aspirin, morphine, metronidazole, GCS, bilirubin, thyroxine. Drug glucuronides, excreted in bile, can be hydrolyzed in the gut by bacteria, producing beta-glucuronidase.

The

liberated

drug of

is some

reabsorbed drugs

and (e.g. oral

undergoes the same fate. This enterohepatic

recirculation chloramphenicol, phenolphthalein,

contraceptives) prolongs their action.

(2) Acetylation. Compounds having amino or hydrazine residues are conjugated with the help of and acetyl rate CoA, of e.g. sulfonamides, shows isoniazid. genetic Multiple genes control the acetyl transferases acetylation polymorphism (slow and fast acetylators).

(3) Sulfate conjugation. The phenolic compounds and steroids are sulfated by sulfokinases, e.g. chloramphenicol, adrenal, and sex steroids.

The two phases of drug metabolism

Synthetic (conjugation) reactions:

(4) Methylation. The amines and phenols can be methylated. Methionine and cysteine act as methyl donors. Examples: adrenaline, histamine,

nicotinic acid.
(5) Ribonucleoside/nucleotide antimetabolites synthesis in is

important for the activation of many purine and

pyrimidine used cancer chemotherapy, e.g. Xeloda.

(6) Only a few drugs are metabolized by enzymes

of intermediary metabolism. Examples: alcohol by dehydrogenases

allopurinol by xanthine oxidase

succinylcholine cholinesterase and procaine by plasma

adrenaline by monoamine oxidase (MAO)

FIRST PASS (PRESYSTEMIC) METABOLISM This refers to metabolism of a drug during its passage from the site of absorption into

systemic circulation. All orally administered

drugs are exposed to drug metabolism in the intestinal wall and liver in different extent. High first pass metabolism: propranolol, salbutamol,

verapamil,

pethidine,

nitroglycerine, morphine, lidocaine.

Excretion is the passage out of systematically absorbed drugs.

Drugs and their metabolites are excreted in:

urine (through the kidney) bile and faeces exhaled air saliva and sweat milk skin

The kidney is responsible for excreting all water soluble substances. Glomerular filtration Glomerular capillaries have to the large pores. All

nonprotein
insoluble)

bound
presented

drugs

(lipid

soluble

or
are

glomerulus

filtrated. Glomerular filtration of drugs depends on their plasma protein binding and renal blood flow.

Glomerular renal failure.

filtration

rate

(g.f.r.)

declines

progressively after the age of 50 and is low in

Tubular reabsorption Lipid soluble drugs filtrated at the glomerulus

back diffuse in the tubules because 99% of

glomerular filtrate is reabsorbed, but nonlipid soluble and highly ionized drugs are unable to do so.

Thus, the rate of excretion of such drugs, e.g. aminoglycoside (amikacin, gentamicin, obramycin) parallels g.f.r. Changes in urinary

pH

affect

tubular

reabsorption

of

partially

ionized drugs: Weak bases ionize more and are less

reabsorbed in acidic urine.

Weak acids ionize more and are less reabsorbed in alkaline urine.

This

principle

is

utilized

for

facilitating

elimination of drugs in poisoning: Urine is acidified in morphine and atropine poisoning.

Urine is alkalized in barbiturate and salicylate

poisoning.

The effect of changes in urinary pH on drug excretion is greatest for a drug having pK values between 5 to 8, because only in this case pH

dependent passive reabsorption is significant.

Tubular secretion is the active transfer of organic acid and bases by two separate nonspecific mechanisms, which operate in the proximal tubules:

Organic

acid

transport
salicylates,

for

penicillins,
uric acid,

probenecid,

sulfinpyrazones, Organic quinine, base transport

nitrofurantoin, for thiazides, cimetidine,

methotrexate, drug glucuronides, etc.

procainamide,

amiloride, etc.

Many drug interactions occur due to competition

for tubular excretion, e.g.:

Aspirin blocks uricosuric action of probenecid and sulfinpyrazone and decreases tubular excretion of methotrexate. Probenecide decreases the urine concentration

of nitrofurantoin, increases the duration of

penicillin action and impairs excretion of methotrexate.

Quinidine decreases renal and biliary clearance

of digoxin by inhibiting efflux carrier P-gp.

Tubular transport mechanisms are not well developed at birth. Duration of action of many drugs (penicillins, cephalospoins, aspirin, etc.)

is longer in neonates. These systems mature

during infancy.

Plasma half live (t1/2) is the time in which the plasma concentration of a drug declines by one half. Drug with long t1/2 can accumulate. Plasma

t1/2 of some drugs:

Adenosine < 2 sec Dobutamine 2 min Benzylpenicillin 30 min Amoxicillin 1 h Paracetamol 2 h Atenolol 7 h Diazepam 40 h Ethosuccimide 54 h Digitoxin 168 h

KINETICS OF ELIMINATION (elimination = metabolism + excretion) Clearance (Cl) of a drug is the theoretical volume of plasma from which the drug is completely removed per unit time:

Cl = Rate of elimination/Plasma concentration

Renal (Clr) or creatinine clearance (Clcr): Clrenal

Curine x Vurine = -------------------Cplasma

First order (exponential) kinetics For majority of drugs the processes involved in elimination are not saturated over the clinically obtained concentrations. These drugs have first order kinetics. Their and rate of elimination is

directly
constant.

proportional
their

to

plasma

drug
remains

concentration

clearance

Zero order (linear) kinetics. In a few cases where the drugs are inactivated by metabolic degradation (such as ethanol, phenytoin, theophylline, salicylates, and warfarin), the time-course of disappearance of

the drug from the plasma does not follow the

exponential or biexponential pattern, but is initially linear.

These drugs are removed at a constant rate

which is independent of plasma concentration. This is often called zero order kinetics.

From the peak plasma concentration the drug is

virtually eliminated from the plasma in 5 t1/2

periods

(1)

(2)

(3)

(4)

(5)