Toxicokinetics

Dosage EffectsSiteof

Action

PlasmaConcen.

PharmacokineticToxicokinetics

PharmacodynamicsToxicodynamics

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DISPOSITION OF CHEMICALS

The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).


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Plasma concentration vs. time profile of a single dose of a chemical ingested orally


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TOXIC RANGE

THERAPEUTIC RANGE

SUB-THERAPEUTIC


Bound Free Free Bound

LOCUS OF ACTION

“RECEPTORS”TISSUE

RESERVOIRS

SYSTEMIC CIRCULATION

Free Drug

Bound Drug

ABSORPTION EXCRETION

BIOTRANSFORMATIONwww.freelivedoctor.com

Transfer of Chemicals across Membranes

• Passive transport determined by:- Permeability of surface

- Concentration gradient

- Surface area

• Permeability depends on:For cell membranes:

- Lipid solubility

- pH of medium

- pK of chemical

For endothelium

size, shape and charge of chemical

PASSAGE ACROSS MEMBRANES

Passive

Facilitated

Active


Weak Acids and Weak Bases

HA <==> H+ + A- B + H+ <==> BH+

[ UI ] [ I ] [ UI ] [ I ]

pKa=pH+log(HA/A-) pKa=pH+log(BH+/B)

pKa = 4.5 (a weak acid)

100 = [ UI ] [ UI ] = 100

pH = 2 pH = 7.40.1 = [ I ] [ I ] = 9990

100.1 = total drug = 10090


Factors Affecting Absorption (G.I., lungs, skin)

• Determinants of Passive Transfer (lipid solubility, pH, pK, area, concentration gradient).

• Blood flow to site.

• Dissolution in the acqueous medium surrounding the absorbing surface.


Factors Affecting Absorption from the GI Tract

• Disintegration of dosage form and dissolution of particles

• Chemical stability of chemical in gastric and intestinal juices and enzymes

• Motility and mixing in GI tract• Presence and type of food• Rate of gastric emptying

Intestinal vs. gastric absorption

FIRST PASS EFFECTwww.freelivedoctor.com

Absorption from the Lungs

• For gases, vapors and volatile liquids, aerosols and particles

• In general: large surface area, thin barrier, high blood flow rapid absorption

• Blood:air partition coefficient –

influence of respiratory rate and blood flow

• Blood:tissue partition coefficient


Absorption of Aerosols and Particles:

1- Particle Size

2- Water solubility of the chemical present in the aerosol or particle

REMOVAL OFPARTICLES

Physical

Phagocytosis

Lymph

Absorption from the Lungs


NasopharyngealRegion

5-30 µm

Trachea

Bronchi

Bronchioles

1-5 µm

Alveolar Region

1 µm

DEPOSITION OF PARTICLES IN THE RESPIRATORY SYSTEM


Absorption from the Skin

• Must cross several cell layers (stratum corneum, epidermis, dermis) to reach blood vessels.

• Factors important here are:

lipid solubility

hydration of skin

site (e.g. sole of feet vs. scrotum)


Other Routes of Exposure

• Intraperitoneal large surface area, vascularized, first pass effect.

• Intramuscular, subcutaneous, intradermal: absorption through endothelial pores into the circulation; blood flow is most important + other factors

• Intravenous


Bioavailability

Definition: the fraction of the administered dose reaching the systemic circulation

for i.v.: 100%for non i.v.: ranges from 0 to 100%

e.g. lidocaine bioavailability 35% due to destruction in gastric acid and liver metabolism

First Pass Effect www.freelivedoctor.com

Bioavailability

Dose

Destroyed in gut

Notabsorbed

Destroyed by gut wall

Destroyedby liver

tosystemiccirculation


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Plasma concentration

Time (hours)

i.v. route

oral route

Bioavailability

(AUC)o

(AUC)iv


PrinciplePrinciple

For chemicals taken by routes other than the i.v. route, the extent of absorption and the

bioavailability must be understood in order to determine whether a certain exposure dose will induce toxic effects or not. It will also explain why the same dose may cause toxicity by one

route but not the other.


• Plasma 3.5 liters. (heparin, plasma expanders)

• Extracellular fluid 14 liters.

(tubocurarine, charged polar compounds)

• Total body water 40 liters. (ethanol)

• Transcellular small. CSF, eye, fetus (must pass tight junctions)

Distribution into body compartments


Distribution

• Rapid process relative to absorption and elimination

• Extent depends on - blood flow

- size, M.W. of molecule- lipid solubility and

ionization - plasma protein binding - tissue binding


Distribution

• Initial and later phases:

initial determined by blood flow

later determined by tissue affinity

• Examples of tissues that store chemicals:

fat for highly lipid soluble compounds

bone for lead


Distribution

• Blood Brain Barrier – characteristics:

1. No pores in endothelial membrane

2. Transporter in endothelial cells

3. Glial cells surround endothelial cells

4. Less protein concentration in interstitial fluid

• Passage across Placenta


100-fold increase in free pharmacologically active concentration at site of action.

NON-TOXIC TOXIC

Alter plasma binding of chemicals

1000 molecules

% bound

molecules free

99.9 90.0

100 1


Chemicals appear to distribute in the body as if it were a single compartment. The magnitude of

the chemical’s distribution is given by the apparent volume of distribution (Vd).

Amount of drug in bodyConcentration in Plasma

Vd =

PRINCIPLEPRINCIPLE


Volume of Distribution

Volume into which a drug appears to distribute with a concentration equal to its plasma concentration


Drug L/Kg L/70 kg

Sulfisoxazole 0.16 11.2

Phenytoin 0.63 44.1

Phenobarbital 0.55 38.5

Diazepam 2.4 168

Digoxin 7 490

Examples of apparent Vd’s for some drugs


KID N EYf iltra tion

secretion(reab sorp tion )

LIVERm etabolism

excretion

LU N GSexhalation

OTH ER Sm other's m ilk

sw eat, sa liva etc .

Elim inationof chem icals from the body


Elimination by the Kidney• Excretion - major

1) glomerular filtrationglomerular structure, size constraints, protein binding 2) tubular reabsorption/secretion- acidification/alkalinization,- active transport, competitive/saturable, organic acids/bases

-protein binding• Metabolism - minor


Nephron Structure

The structure of the nephron (from A.C. Guyton, Textbook of Medical Physiology, Philadelphia, W.B. Saunders Co.; 1991www.freelivedoctor.com

Elimination by the Liver

• Metabolism - major

1) Phase I and II reactions 2) Function: change a lipid soluble to more water soluble molecule to excrete in kidney

3) Possibility of active metabolites with same or different properties as parent molecule

• Biliary Secretion – active transport, 4 categories


The enterohepatic shunt

Portal circulation

Liver

gall bladder

Gut

Bile

duct

Drug

Biotransformation;glucuronide produced

Bile formation

Hydrolysis bybeta glucuronidase


EXCRETION BY OTHER ROUTES• LUNG - For gases and volatile liquids by diffusion.

Excretion rate depends on partial pressure of gas and blood:air partition coefficient.

• MOTHER’S MILK a) By simple diffusion mostly. Milk has high lipid content and is more acidic than plasma (traps alkaline fat soluble substances). b) Important for 2 reasons: transfer to baby, transfer from animals to humans.

• OTHER SECRETIONS – sweat, saliva, etc.. minor contribution


CLINICAL TOXICOKINETICS

Quantitative Aspects of Toxicokinetics


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Influence of Variations in Relative Rates of Absorption and Elimination on Plasma

Concentration of an Orally Administered Chemical


Elimination• Zero order: constant rate of elimination

irrespective of plasma concentration.

• First order: rate of elimination proportional to plasma concentration. Constant Fraction of drug eliminated per unit time.

Rate of elimination = constant (CL) x Conc.


Zero Order Elimination Pharmacokinetics of Ethanol

• Mild intoxication at 1 mg/ml in plasma• How much should be taken in to reach it?

42 g or 56 ml of pure ethanol (Vd x Conc.)Or 120 ml of a strong alcoholic drink like whiskey

• Ethanol has a constant rate of elimination of 10 ml/hour

• To maintain mild intoxication, at what rate must ethanol be taken now? at 10 ml/h of pure ethanol, or 20 ml/h of drink.

RARELY DONE

DRUNKENNESS


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Ct = Co e-Kel.t

lnCt = lnCo – Kel .t

logCt = logCo - Kel . t 2.303

dC/dt = k

y = b – a.x

First Order Elimination


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Zero Order Elimination

logCt = logCo - Kel . t 2.303


Time

Plasma Concentration

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C0

Distribution equilibrium

Elimination only

Distribution and Elimination

Plasma Concentration Profile after a Single I.V. Injection


lnCt = lnCo – Kel.t

When t = 0, C = C0, i.e., the concentration at time zero when distribution is complete and

elimination has not started yet. Use this value and the dose to calculate Vd.

Vd = Dose/C0


lnCt = lnCo – Kel.t

When Ct = ½ C0, then Kel.t = 0.693. This is the time for the plasma concentration to reach half

the original, i.e., the half-life of elimination.

t1/2 = 0.693/Kel


PrinciplePrinciple

Elimination of chemicals from the body usually follows first

order kinetics with a characteristic half-life (t1/2) and fractional rate constant (Kel).


First Order Elimination

• Clearance: volume of plasma cleared of chemical per unit time.Clearance = Rate of elimination/plasma conc.

• Half-life of elimination: time for plasma conc. to decrease by half.

Useful in estimating: - time to reach steady state

concentration. - time for plasma conc. to fall after exposure stopped.


Rate of elimination = Kel x Amount in bodyRate of elimination = CL x Plasma Concentration

Therefore,Kel x Amount = CL x Concentration

Kel = CL/Vd

0.693/t1/2 = CL/Vd

t1/2 = 0.693 x Vd/CLwww.freelivedoctor.com

PrinciplePrinciple

The half-life of elimination of a chemical (and

its residence in the body) depends on its

clearance and its volume of distribution

t1/2 is proportional to Vd

t1/2 is inversely proportional to CL

t1/2 = 0.693 x Vd/CL


Multiple dosing

• On continuous steady administration of a chemical, plasma concentration will rise fast at first then more slowly and reach a plateau, where:

rate of administration = rate of elimination ie. steady state is reached.

• Therefore, at steady state:Dose (Rate of Administration) = clearance x plasma conc.

orsteady state conc. = Dose/clearance


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Toxic level

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Concentration due to a single dose

Concentration due to repeated doses

The time to reach steady state is ~4 t1/2’s


Pharmacokinetic parameters

• Vol of distribution V = DOSE / Co

• Plasma clearance Cl = Kel .Vd

• plasma half-life (t1/2) t1/2 = 0.693 / Kel or directly from graph

• Bioavailability (AUC)x / (AUC)iv


But Conc. x dt = small area under the curve. For total amount eliminated (which is total given or the

dose if i.v.), add all the small areas = AUC. Dose = CL x AUC and Dose x F = CL x AUC

dX/dt = CL x Conc.

dX = CL x Conc. x dt


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Bioavailability (AUC)o

(AUC)iv=

i.v. route

oral route


Daily Dose (mg/kg)

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Variability in Pharmacokinetics


PRINCIPLEPRINCIPLE

The absorption, distribution and elimination of a chemical are

qualitatively similar in all individuals. However, for several

reasons, the quantitative aspects may differ considerably. Each person

must be considered individually and treated accordingly.


THE DOSE-RESPONSE RELATIONSHIP

The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).


Toxicokinetics

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