Lecture 29: Recap - bioavailability, dissolution and membrane transport

what is pharmacodynamics?

what the drug does the to body

what is pharmacokinetics?

what the body does to the drug

what is bioavailability?

a measure of the amount of drug that reaches its site of action and the rate at which it gets there

• important for comparing dosage forms

what are the determinants for pharmacokinetics?

• Liberation(release from dosage form)

• Absorption

• Distribution

• Metabolism

• Excretion

After extra vascular administration, what are the 2 steps the drug appearance in blood demands?

1. release: drug dissolves at administration site

2. absorption: drug crosses biomembrane to reaach blood

   • slowest step controls overall rate of absorption

Explain what is shown on the graph here

1. drug is rapidly released but only a small amount passes through the membrane so its typically hydrophilic molecules. permeation is the limiting factor

2. drug is poorly soluble but has good permeation which is typical for lipophilic molecules

what does the process of dissolution of a solid crystal in a liquid involve?

1. solvation of a drug at crystal surface to create a stagnant layer of saturated solution

2. diffusion of dissolved molecules across this layer into bulk solution

   • observed rate depends on slowest step

what is the overall rate of dissolution at constant temp equation?

Noyes-whitney equation

• S= surface area of particle

how can the solubility(Cs) of a weakly acidic drug be predicted?

• pH of solution

• pKa

• Solubility of free Unionised form of drug(So)

how can the solubility(Cs) of a weakly basic drug be predicted?

• pH of solution

• pKa

• solubility of free unionised form of drug(So)

what are the 2 methods of membrane transport of drug?

1. transcellular pathway

2. paracellular pathway

what are the 4 pathways of transcellular absorption(Major)?

• passive diffusion

• aqueous pore

• facilitated diffusion

• active transport

how does passive diffusion take place in transcellular absorption?

• main pathway of drug absorption

• solutes diffuse down a conc gradient

• must partition into the lipid bilayer and out into cytoplasm

how do solutes move across aqueous pores in transcellular absorption?

• continuous

• hydrophilic channel created by aquaporin proteins

• allows transport of small neutral solutes such as urea and glycerol

how does facilitated diffusion take place in transcellular absorption?

• selective

• carrier mediated transport of drug down conc gradient

how does active transport take place in transcellular absorption?

• selective

• carrier mediated transport of drug down or against conc gradient

• needs energy from ATP

what happens to drug molecules not in equilibrium?

it moves towards equilibrium which means flow(flux) must occur

what is the formula for flux

F= C x V x A

• conc

• velocity

• area

what is ficks first law equation?

what happens to flux as surface area increases (A)?

• flux increases

what happens to flux as membrane thickness increases (DeltaX)?

• flux decreases(inversely proportional)

what happens to flux as conc gradient increases (C1-C2)?

• flux increases(directly correlated)

ficks first law of diffusion:

what is the partition coefficient?

it quantifies the distribution of drug between membrane and aqueous phases which it separates

octanol-water partition coefficient(Log P) is often used to characterise a drugs lipophilicity

K=Coil/Cw

K= drugs relative affinity for oil compared to water

how does a drugs lipophilicity affect its ADE?

• has to be lipophilic to cross cell membranes

• too lipophilic may be deposited in fatty tissues

features of the octanol water partition coefficient:

e.g conc of drug is 10x more soluble in octanol than water if P=10 and logP=1

most drugs are weak acids or bases so they exist in a solution as an equilibrium of unionised and ionised forms depending on the pH of the environment and the pKa of the drug

what are the pH partition hypothesis limitations?

doesnt take into account:

• type of epithelium

• surface area of absorption site

• active transport of drugs

what is lipinskis rule of 5

predicts good oral bioavailability

• molecular weight</500

• log P </ 5

• no more than 5 H bond donors

• no more than 10 H bond acceptors