DISTRIBUTION

dr. Yunita Sari Pane, MSiD t Ph l & Th tiDept. Pharmacology & Therapeutic

FK - USU

DosePharmacokinetic

D C t ti i

ABSORBTION

DISTRIBUSITIONDrug Concentration in

sistemic circulation

DISTRIBUSITIONDrug in tissue

ELIMINATION

Drug concentration in site drug action

Metabolism or Excretion

Pharmacologyc effecteffect

Response

Pharmacodynamic

Toxicity Efficacy

• Drug distribution is achieved primarilyDrug distribution is achieved primarily through the circulatory system; a minor component is contributed by the lymphaticcomponent is contributed by the lymphatic system.

• The concentration of drug in plasma is ft d t d t i th ti doften used to determine therapeutic drug

levels, because the amount of drug that is t ll t k b th t t iactually taken up by the target organ is

difficult to measure.

• The Volume of Distribution of a drug (Vd)represents the fluid volume that would berepresents the fluid volume that would be required to contain the total amount of absorbed drug in the body at a uniformabsorbed drug in the body at a uniform concentration equivalent to that in the plasma at a steady state. p y

• The capacity of bloodstream and the variousThe capacity of bloodstream and the various body organs and tissues to take up and retain a drug depens on both the volume g p(mass) of the tissue and the density of specific and non specific binding sites for the d i hi h idrug within that tissue.

Plasma Protein BindingPlasma Protein Binding

• Plasma protein binding tends to reducePlasma protein binding tends to reduce the availability of a drug for diffusion or transport into the drug’s target organtransport into the drug s target organ because, in general, only the free or unbound form of the drug is capable ofunbound form of the drug is capable of diffusion across membranes.

• Plasma protein binding may also reduce• Plasma protein binding may also reduce the transport of drugs into such non vascular compartments as adipose tissuevascular compartments as adipose tissue and muscle

• Theoretically, plasma protein binding could be important as a mechanism for somebe important as a mechanism for some drug drug interactions.

MODELING THE KINETICS AND THERMODYNAMICS OF DRUG DISTRIBUTIONTHERMODYNAMICS OF DRUG DISTRIBUTION

• Most drugs are distributed rapidly from the• Most drugs are distributed rapidly from the systemic circulation (intravascular compartment) to other compartments in thecompartment) to other compartments in the body.

• This distribution phase results in a sharp decrease in the plasma drug concentration shortly after intravenous administration of a drug bolus.

• Even after the drug equilibrates among its ti i th l dtissue reservoirs, the plasma drug concentration continues to decline because f d li i ti f th b dof drug elimination from the body.

• The rate of decline of plasma drug concentration during the elimination phase is g pslower than that during the distribution phase, because drug in the tissue reservoir p , gis in equilibrium with that in the intravascular compartment, and therefore, drug can diffuse p , , gfrom the tissue back into the blood

Th t d f d t b t k bThe tendency for a drug to be taken up by adipose and muscle tissue during the di t ib ti h lt i t f thdistribution phase result in a set of the dynamic equilibria among drug

t ti i th i b dconcentrations in the various body compartments.

• The rapid decline of plasma drugThe rapid decline of plasma drug concentration after administration of an intravenous bolus of drug can beintravenous bolus of drug can be approximated more accuratelyby using a four compartement model consisting offour compartement model consisting of blood and vessel-rich, muscle-rich, and adipose-rich tissuesadipose rich tissues.

D t d t it f th l i h• Drugs tend to exit from the vessel-rich group first, followed by the muscle group and then th f tthe fat group.

• Delivered of drug depend on:- Blood flow- Hydrophobicity of drug- Capillary permeability- Capillary permeability- Affinity to plasma protein or tissue