Give the log P, relative molecular mass and pKa of paracetamol. Explain how each of these would affect the absorption of a solution of paracetamol from the small intestine.
Paracetamol is an OTC analgesic which is widely used for minor pain. Before the drug can have a therapeutic effect it must first be absorbed through the wall of the intestine and into the blood. The speed and efficiency of the absorption is determined by several factors which include the pKa, log P and molecular mass of the drug. In this essay i will discuss these factors related to paracetamol and how this determines its absorption.
Small lipophilic molecules are usually absorbed in to the body across the lipid bilayer and the maximum molecular weight for this transmembrane transport is usually around 500 Da (1). The smaller the molecular mass, the faster the rate of absorption as it is easier for the molecule to diffuse into the membrane and partition out into the cell. The relative molecular mass of paracetamol is 151.2 (2) which is relatively small for a drug molecule. This means that it is more easily absorbed than larger drug molecules.
Log P is the log of the partition coefficient of a drug between an organic solvent such as octanol and an aqueous phase, at a Ph where all the drug molecules are in their unionised form. It is a measure of the lipophilicity of the drug and a higher value represents a more lipophilic compound. This is important when looking at the absorption of a drug as the more lipophilic the molecule, the easier it will dissolve in the lipid bilayer. The log P of paracetamol is 0.49 (3), which is relatively small and represents a low percentage absorption. The low lipophilicity of paracetamol is due to the fact that it can form hydrogen bonds with surrounding water molecules.
In the small intestine the pH is about 6.5 so it is likely that a drug molecule will be in both the ionised and neutral form. It is therefore also important to consider the pKa of the drug to work out the percentage of the compound that will be ionised. An ionised molecule is hydrophilic so will be fully dissolved in the aqueous gut content and will not dissolve in the lipid membrane. Consequently, the higher the percentage of ionised drug, the less that will be absorbed. Paracetamol has a pKa of 9.5 (4). Using the Henderson-Hasselbalch equation and a pH of 6.5 in the small intestine, the percentage of paracetamol that will be ionised is 0.01%. This shows that the majority of the drug will be in the neutral form which increases absorption.
Overall I think that paracetamol is an effective drug molecule because it is easily absorbed and therefore brings about a therapeutic effect quickly. It has a low molecular mass and is almost completely unionised in the small intestine which allows it to be absorbed more easily. Although the log P is low, which means that the molecule is less lipophilic, this is outweighed by the other factors. Also, the dosage can always be increased to compensate for a lower percentage absorption.
1) Hillary, A., Lloyd, A., Swarbrick, J., 2001, Drug Delivery and Targeting for Pharmacists and Pharmaceutical Scientists, London, Taylor and Francis, Page 27
2) http://chrom.tutms.tut.ac.jp/JINNO/DRUGDATA/01acetaminophen.html (Accessed 21/02/2010)
3)http://www.pharmacopoeia.co.uk.ezproxy.brighton.ac.uk/bp2010/ixbin/bp.cgi?a=display&r=6Yyc_VVMCVJ&n=6&id=6800&tab=search (Accessed 21/02/2010)