4: Drug Absorption

what is the first essential step in the dose-response relationship (assuming a drug wasn’t administered locally/intravascularly)

drug absorption into systemic circulation

what are two important aspects of drug absorption into systemic circulation

1. how much is absorbed (F)

2. how quickly it’s absorbed (ka)

What are the four sites of oral absorption? Which is the main site? What do they all contain?

1. mouth

2. stomach

3. small intestine (main)

4. colon

all contain digestive enzymes

passive absorption, what type of kinetics do they follow?

transcellular, paracellular

typically follow 1st-order kinetics

active absorption

uptake and efflux transporters

how do uptake transporters impact absorption

increase

how do efflux transporters impact absorption

decrease

bioavailability (F)

fraction of dose that reaches systemic circulation

Fa

dose fraction that escapes all adverse events up to apical side of GI lumen

Fg

dose fraction that escapes metabolism in GI membrane

Fh

fraction of drug entering liver (after GI absorption)

what form must drugs be in to pass through the GI membrane

soluble form (solutions give faster dissolution)

what particle size gives faster dissolution

smaller

what solid state is more metastable? how does this impact solubility

amorphous (more metastable compared to crystalline); increases solubility

acidic hydrolysis and how to avoid?

acid destroys oral dose

use enteric-coated, use antacids before taking

unionized or ionized gives better dissolution?

ionized

when are weak acids more ionized

higher pH

when are weak bases more ionized

lower pH

how do large meals impact acid

stimulate acid production

how does food impact stomach emptying and what does this mean for acid labile drugs

food delays stomach emptying → acid labile drugs more degraded

what does bile do to drugs

food stimulates bile, which solubilizes drugs

how do CYP3A4 inhibitors impact intestinal extraction

decrease intestinal extraction (most of them also decrease p-gp efflux) → both increase Fg

grapefruit juice

CYP3A4 inhibitor → decreases metabolism → increases drug exposure

low Fg impacts DDI potential how

increases risk of DDI potential (but can help increase bioavailability of CYP3A4 substrate)

extraction ratio (E)

fraction of dose that got metabolized/extracted (F = 1 - E)

what does changing Ka affect & not affect

affects: Tmax, Cmax

doesn’t affect: AUC

increasing Ka does what

increase Cmax, lower Tmax

decrease F results in what

decrease Cmax, decrease AUC

BCS Class 1

high solubility

high permeability

(good absorption)

BCS Class 2

low solubility (limited by dissolution)

high permeability

BCS Class 3

high solubility

low permeability (limited by permeation rate)

BCS Class 4

low solubility

low permeability

(poor absorption, high variability)

BCS high solubility

highest dose strength is soluble in <250mL

BCS high permeability

>90% of administered dose absorbed in humans

rapid dissolution

drug product dissolved ≥85% within 30 minutes

pH: 1, 4.5, 6.8