3: Passage of Drugs Through Membranes

paracellular pathway

through pores/junctions between membrane cells

Between paracellular pathway and transcellular pathway, which is less efficient and why?

paracellular; low contact area

paracellular permeability traits

small, water-soluble molecules

transcellular pathway

through cell/membrane

transcellular permeability traits

small, lipophilic molecules

what drugs can participate in passive diffusion?

free, unbound drug

partition coefficient

(Km, P)
balance between hydrophobicity/hydrophilicity of a compound (unionized form)

LogP <0

too hydrophilic

LogP >3.5

too hydrophobic

(as logP increases, so does hydrophobia)

P <1

too hydrophilic

P >3000

too hydrophobic

HCl

acid counter ion (drug is a weak base)

phospate

acid counter ion (drug is a weak base)

sulfate

acid counter ion (drug is a weak base)

mesylate

acid counter ion (drug is a weak base)

sodium

basic counter ion (drug is a weak acid)

potassium

basic counter ion (drug is a weak acid)

calcium

basic counter ion (drug is a weak acid)

ion trapping

ionized drugs can't partition, get trapped where they are

amine group

(-NH2, -NHR, -NR2)

weak base

carboxylic acid group

(-COOH)

weak acid

phenol group

(Ar-OH)

weak acid

sulfonamide

(SO2-NH-R)

weak acid

Do ionized or un-ionized drugs cross biological membranes?

un-ionized (protonated)

What is the state of most drugs in biological fluid?

partially ionized

Weak acids at low pH (high H+)

more un-ionized

Weak acids at high pH (low H+)

more ionized

Weak bases at high pH (low H+)

more ionized

Weak bases at low pH (high H+)

more ionized

What happens to a drug’s permeability if it is more un-ionized?

more un-ionized = more permeability

acid H-H equation

pKa = pH+log10([HA]/[A-])

base H-H equation

pH = pKa+log10([B]/[BH+]}

find ionized amount for acid

I = U*10^(pH-pKa)

find unionized amount for base

U = I*10^(pH-pKa)

OATP in liver

uptake, elimination

OATP in intestine

uptake, absorption

OAT in kidney

uptake, elimination

OCT1 in liver

hepatic uptake

OCT2 in kidney

uptake, elimination

efflux transporters (p-gp) impact on absorption

inhibit absorption (act as reverse pump)

what happens if p-gp substrate is administered with a p-gp inhibitor

substrate concentration increases

total drug exposure increases

absorption increases

what happens if p-gp substrate is administered with a p-gp inducer

substrate concentration decreases

total drug exposure decreases

absorption decreases

endocytosis

moving molecules into cell (phago, pino)

phagocytosis

engulfment of larger particles

pinocytosis

engulfment of smaller particles

exocytosis

moving molecules out of cell

transcytosis

transporting molecules across cell interior & ejecting to the other side