role of physiochemical properties in DMPK (ADME stuff i think) Flashcards
what is an enterocyte
type of intestinal cell that lines the small intestine and is responsible for absorbing nutrients from food
what problems does a drug need to overcome to get to the membrane of enterocyte
solubility in aqueous environment of GIT lumen- drug must solubilise before absorbed, solubility depends on hydrophobicity and pKa of drug
presence of unstirred water layer and mucus-static layer, diffusion slower, larger and hydrophobic drug also slower
chemical enzymatic stability in GIT
what type of drug arrives at intestinal epithelium membrane easily
small, stable, hydrophilic, ionised
most important factor to reach membrane of intestinal epithelium
solubility in aq environment
describe the GIT epithelium
-small intestine epithelium=microvilli for increased absorption
-stomach epithelium doesnt have microvilli, lower absorptive area
-tight junctions=junction between epithelial cells, here specific proteins in two adjacent membranes make direct contact across intercellular space
(drawing in notes)
describe absorption by intercellular route vs transcellular
intercellular=less common and less important than transcellular transport, some small hydrophilic (highly water soluble) molecules can be absorbed this way
transcellular=crosses both membranes, absorbed from intestinal lumen into systemic circulation, multiple barriers crossed
whats the main mechanism of absorption described by
ficks law
what is ficks law
R= -D x A x ∆𝐶/∆X
R=diffusion rate (moles/s)
D=diffusion coefficient, constant for specific molecule in specific conditions
A=area of membrane where diffusion is occuring
∆𝐶=conc difference between outside and inside of membrane
∆X=thickness of membrane
what physiochemical properties determine diffusion coefficient for a specific molecule
partition coefficient (P) and molecular weight
what is partition coeffient
indication of lipophilicity of a drug
-describes how drug distributes itself between a pair of solvents in unionised form (aq phase and oily solvent like octanol)
-hydrophobic drugs dissolve mainly in the oil, has high P
-hydrophilic drugs mainly in water, low P
-to be absorbed, drug should have some solubility in water and some in oily membrane
why are drugs with low/high partition coefficient poorly absorbed
-drugs with low P are poorly absorbed bc they cant dissolve in oily cell membrane
-high P drugs cant absorb bc they cant dissolve in intestinal lumen, cant reach membrane
what is the pH partition hypothesis on importance of pKa
-drug molecules are usually weakly ionisable species (weak acids/weak bases)
-drugs penetrate lipophilic membrane in unionised/nonpolar state
-therefore pH in intestinal lumen is very important in determining absorption across membrane
what is the pH partition hypothesis on weak acid vs weak base
-an acidic drug would penetrate membrane better from acidic environment (stomach) but solubility would be higher in basic environment (small intestine)
-basic drug would penetrate membrane better from basic environment (small intestine) but solubility would be higher in acidic environment (stomach)
-however due to high absorptive area and good perfusion most drugs will be absorbed mostly in small intestines
describe transporters in drug absorption
-saturable, limited number of transporters per cell
-absorbance window-specific ligands taken up in specific parts of gut
-efflux transporter p-glycoprotein mostly for lipophilic/amphiphilic compounds
stuff about P-glycoprotein
what type of transporter is it, important barrier in what type of absorption, expressed where
-ATP dependent transporter capable of transportation of very wide variety of drugs OUT of cell
-one of most important barriers in intestinal abs of drugs
-most p-glycoprotein substrates are lipophilic or amphiphilic
-expressed in intestinal epithelium, liver, brain, adrenal gland, kidney
-highly expressed in some cancer cellls, responsible for multidrug resistance cancer cells
-works with CYP450 3A4
drugs that penetrate enterocyte barrier easily are…
small, hydrophobic, unionised, not a substrate to P-glycoprotein, not a substrate to metabolising enzymes in intestinal wall, substrate to influx transporter
(opposites for drugs with problems penetrating)
lipinski’s rule of 5
- not more than 5 H bond donors (nitrogen or oxygen atoms with one or more H atoms)
- not more than 10 H hydrogen bond acceptors
- molecular mass<500 daltons
- octanol water partition coefficient (LogP)<5
what is BCS high solubility criteria
drug substance is highly soluble when highest dose strength is soluble in 250ml or less of aq media over a pH of 1-7.5 at 37c
what is BCS high permeability criteria
extent of absorption in humans is determined to be >90% of administered dose based on mass balance determination
metabolism vs direct excretion
-after administsration, most drugs undergo chemical changes before excretion, changes are called metabolism
-elimination of drugs from body occur by excretion and metabolism
-metabolism=major route of elimination of drugs from body
what is first pass metabolism, where can it occur, enzymes involved
metabolism during first passage across intestinal wall and through liver reduces amount that reaches general circulation
-drug can undergo first pass metabolism in gut wall, liver or both
-gut contains many enxymes found in liver especially CYP3A4 and several glucuronyl transferases
-drugs that undergo extensive first-pass metabolism in gut wall and liver, there is often a very large effect of induction/inhibition of enzymes on their bioavailability
-first-pass metabolism can be saturable for some drugs (bioavailability will be higher with higher dose)
draw the BCS high solubility criteria
notes
