Absorption of a solution of a drug from the small intestine requires the drug to

pass across the lipoidal membrane of the gastrointestinal epithelium. Lipinski’s

Rule of 5 states that for good absorption the molecular weight of a drug must be
less than 500 and the log of the partition coefficient (log P) must be less than 5.
This means that a drug needs to be small and lipid soluble for good absorption to
occur. The pKa (the negative log of the acid dissociation constant) of a drug is
also a determining factor for its absorption. The pKa indicates whether the drug
will be ionised or unionised in a certain environment. Most drugs are more
lipophilic in their unionised form.

Paracetamol is absorbed from the gastrointestinal tract. It has a relative

molecular mass of 151.2 and is therefore small enough to pass across lipoidal
membranes.

The log P of paracetamol is 0.49 . This gives an indication of its lipophilicity i.e.
whether paracetamol is likely to partition across a lipid membrane or not. The log
P of paracetamol is greater than 0 but less than 5 suggesting that it is lipid
soluble and will pass across a lipoidal membrane.

Paracetamol is a weakly acidic drug with a pKa of 9.5 . The degree of ionisation
of a drug is dependent on the pKa of the drug and the pH of the environment it is
present in. The pH in the small intestine ranges from 6 to 7.5 which is far more
basic (alkaline) than the environment in the stomach. This indicates that as the
drug moves further into the small intestine, the degree of ionisation increases
and more of the ionised form is produced.

A- + H+ ←
HA

(ionised form) (in a basic environment)

(unionised form)

The unionised form of the drug is more lipid soluble and therefore will be
absorbed into the epithelium lining the small intestine. There will always be
some unionised form of the system needs to remain in equilibrium and this
unionised form will be absorbed into the lumen of the small intestine. As the
unionised form is absorbed, its concentration in the lumen of the small intestine
decreases so in order to achieve equilibrium more of the unionised form is
produced. Also, the concentration of the unionised drug is always smaller in the
epithelial cells because the drug partitions into the blood stream and is carried
away by the blood. Therefore, the unionised form of paracetamol will be
continuously be moving down its concentration gradient and thus will be
absorbed. The small intestine is very long and so the drug remains in that
environment for a long period of time allowing for most of the paracetamol to be
absorbed.

Paracetamol being a small, lipophilic, weakly acidic drug can easily pass across a
lipid membrane and therefore makes absorption form the small intestine
possible.