Pharmacokinetics DISTRIBUTION

Dr. Yunita Sari Pane, MSi

Department of Pharmacology and Therapy Universitas Sumatera Utara

DISTRIBUTION The transport of a drug in the body by the bloodstream to its site of action

Distribution
Absorbed drugs leave capillary wall quickly and freely (via filtration and diffusion) to enter interstitial fluid; blood flow being important in the regional distribution of drugs
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 Areas of rapid distribution : heart, liver, kidney, brain

Areas of slow distribution: muscle, skin, fat DISTRIBUTION dependent upon tissue permeability, blood flow, perfussion rate of the tissue , drug binding of plasma protein and tissue

Drug Distribution
Drug transfer to various tissues
-- depends on drug lipophilicity and blood flow

Drug barriers
-- e.g. blood-brain barrier, placenta

Drug binding to plasma proteins

-- bound drugs are pharmacologically inactive -- unbound drugs are free to distribute to target tissues -- different drugs may compete for binding to plasma proteins and displace each other from binding sites

 Binding to plasma proteins (mostly to albumin and, for basic drugs, a1acid glycoprotein)
major distribution site highest drug concentrations usually found in blood; serve as drug depots, thus prolonging half-life of drugs pharmacologic effects and toxic manifestations affected by hypoalbuminemia and copresence of other drugs also bound effectively to albumin

 Central nervous system: permeable to lipid-soluble drugs only; limited permeability to water-soluble drugs when inflamed Placental transfer: limited by blood flow, not by a "barrier"

 Fat tissue: depot for thiopental and chlorinated hydrocarbon insecticides (e.g., DDT) Sites for metabolism and excretion: liver, kidney, intestine, lungs Redistribution: especially important for IV injection of lipophilic drugs
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LOCUS OF ACTION RECEPTORS Bound Free

TISSUE RESERVOIRS Free Bound

ABSORPTION

Free Drug Bound Drug CIRCULATION

SYSTEMIC

EXCRETION

BIOTRANSFORMATION

Saturation of Protein Binding Sites

Drug displacement from protein binding sites

Plasma Protein Binding

consequence of drug displacement
an increase in free drug concentration of the displaced drug an increase in drug effect (be cautious when using a drug of low T.I.) a decrease in the duration of action of the displaced drug because more free drugs are available for elimination

Time Course of Drug Action

General rules Compartment models
Single-compartment Multiple-compartment

Exceptions to general rules

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General rules
Plasma concentration related to degree of receptor binding, thus magnitude of drug effect Disposition processes usually first order Elimination usually slower process than absorption or distribution

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 First-order process:
dC/dT = kC (constant fraction)

Zero-order process:
dC/dT = k (constant amount)

Capacity limited process:

low C, first-order; high C, zero-order

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One Compartment IV Bolus Pharmacokinetic Model

Assumptions drug is mixed instantaneously in blood drug in the blood is in rapid equilibrium with drug in the extravascular tissues drug elimination follows first order kinetics

Single compartment model: no absorption, first-order elimination

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One Compartment IV Bolus Pharmacokinetic Model

rate of concentration change at each time point:
dCp = k Cp dt . (1)
Cp : plasma drug concnetration k : elimination rate constant

One Compartment IV Bolus Pharmacokinetic Model

Ct = C0 e k t . (2)

Ct : plasma concentration at time t C0 : plasma concentration at time 0

One Compartment IV Bolus Pharmacokinetic Model

k t log Ct = log C0 . (3) 2.303

Ct : plasma concentration at time t C0 : plasma concentration at time 0

Volume Distribution
Vd is a parameter that indicates the volume of drug distribution in the body with high levels of plasma or serum. Vd do not need to show the actual volume of drug distribution but only the volume of the imagination in which the body is considered as a compartment that consists of plasma or serum, and Vd linking the amount of drug in the body with the levels in plasma or serum.

Vd = X/C = Div/Co(iv) = F.Doral/Co (oral)

X = amount of drug in the body C = drug levels in plasma or serum Div = drug dose on intravenous administration Doral = dose of the drug on oral administration F = fraction of oral dose reaching the systemic blood circulation in active form = bioavailability oral Co = levels of plasma or serum at time t = 0

Vd amount determined by the size and body composition, CV function, the ability of drug molecules into various body compartments, and the degree of drug binding to plasma proteins and with various networks. Drugs that accumulate in the tissues, so levels of drug in plasma is very low, but has a very large Vd (eg digoxin)

whereas drugs that bound strongly to plasma proteins so that the plasma levels high enough to have a small Vd (eg warfarin, tolbutamide, and salicylate

One Compartment IV Bolus Pharmacokinetic Model

Apparent volume of distribution (Vd ) apparent volume that the drug is distributed into not a physiological volume

X Vd = = drug conc. In plasma Cp

amount of drug in the body
DOSE

or

Vd = C0

. (4)

One Compartment IV Bolus Pharmacokinetic Model

DOSE

Vd = C0

. (4)

substitute (4) to (3), I.e. Ct = C0 e k t

DOSE

Ct = e k t Vd

. (5)

One Compartment IV Bolus Pharmacokinetic Model

Half-Life of Elimination ( t 1/2 )
time taken for the plasma concentration to fall to half its original value 0.693 = k

t 1/2

. (6)

One-compartment pharmacokinetics (single dose, IV)

Cp = plasma drug concentration k el = elimination constant

C0 = plasma concentration at time zero elimination half-life t 1/2 = t 2 - t 1

One Compartment IV Bolus Pharmacokinetic Model

Drug clearance ( CL ) a measure of the efficiency with which a drug is removed from the body k CL = = Cp Cp
rate of elimination amount of drug

= Vd k

. (7)

CL total = CL kidney + CL liver + CL others

One Compartment IV Bolus Pharmacokinetic Model

Bioavailability ( F )

measures the extent of absorption of a given drug, usually expressed as fraction of the administered dose intravenous injection, by definition, has a bioavailability of 100%
AUC CL

F =
DOSE

.. (8)

AUC : area under the conc.-time curve

Bioavailability
Plasma concentration

140 120 100 80 60 40 20 0 0 2

i.v. route

(AUC)o (AUC)iv

oral route

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Time (hours)

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Multiple IV Bolus Dose Administration

drug accumulation occurs when repeated doses are given before the drug is completely eliminated
repeated drug administration at dose intervals (t ) will give a steady state with the plasma concentration fluctuating between a maximum (Cmax) and a minimum (Cmin ) value

Combined Infusion and Bolus Administration

to achieve a therapeutic concentration more quickly is to give a loading dose by rapid IV injection and then start the slower maintenance infusion

Loading dose = Css Vd

........... (9)

Maintenance dose = CL Cp t . (10)

 Drug disappearance
usually follows first-order kinetics (exponential decay), with a constant fraction (not amount) of drug being eliminated per unit of time the process is independent of the kind and amount of drug half-life (T1/2), not dose, is the primary factor in prolonging drug effects
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Multicompartment models
combine kinetics of redistribution and elimination provide best description of drugs with high lipid solubility and drugs given intravenously

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Redistribution of thiopental after intravenous injection

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Multi-compartment Pharmacokinetic Model

the drug appears to distribute between 2 or more compartments
the drug is not instantaneously equilibrated in various tissues rapidly perfused tissues often belong to the central compartment

slowly perfused tissues belong to the peripheral compartment

Two-compartment pharmacokinetics (single dose, IV)

central compartment (rapid)

t 1/2 a

peripheral compartment (slow) t 1/2

Two-compartment model

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DRUGS DISTRIBUTION
Factors influence drug distribution
1- Permeability of drug to biological membranes
Blood brain barrier Testicular barrier Placental barrier

- LIPID SOLUBLE DRUGS

- They have large Vd (volume of distribution)

2- Extent of plasma protein

- Highly protein bound stay in circulation & also have large Vd
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DRUGS DISTRIBUTION
Factors influence drug distribution
- Drugs with large Vd have the following properties
High protein binding High lipid solubility High affinity to other tissues such as bone & liver
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DRUGS DISTRIBUTION
Factors influence drug distribution
3 - Availability of transport mechanism
- passive diffusion: The drug must be in unionized form - Active transport: require ATP - Facilitative diffusion: it requires carrier but without energy such vit B12, glucose and amino acid - ion pair transport: the ionic compound combines reversibly with endogenous compound such as MUCIN in GIT

4 - Regional pH
- breast milk more acidic than blood: Weak base drugs accumulate in breast milk
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DRUGS DISTRIBUTION
Factors influence drug distribution
4- Rate of blood flow to tissues
- Skeletal muscles have high blood flow

5- Regional pH
- breast milk more acidic than blood: Weak base drugs accumulate in breast milk

6- Tissues mass
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ended