The medicinal chemist Christopher Lipinski and his colleagues analysed2 the physico-chemical properties of more than 2,000 drugs and candidate drugs in clinical trials, and concluded that a compound is more likely to be membrane permeable and easily absorbed by the body if it matches the following criteria:
Its molecular weight is less than 500.
The compound's lipophilicity, expressed as a quantity known as logP (the logarithm of the partition coefficient between water and 1-octanol), is less than 5.
The number of groups in the molecule that can donate hydrogen atoms to hydrogen bonds (usually the sum of hydroxyl and amine groups in a drug molecule) is less than 5.
The number of groups that can accept hydrogen atoms to form hydrogen bonds (estimated by the sum of oxygen and nitrogen atoms) is less than 10.
The rules, based on the 90-percentile values of the drugs' property distributions, apply only to absorption by passive diffusion of compounds through cell membranes; compounds that are actively transported through cell membranes by transporter proteins are exceptions to the rule. Due in no small part to their simplicity, the Lipinski criteria are widely used by medicinal chemists to predict not only the absorption of compounds, as Lipinski originally intended, but also overall drug-likeness.
Paul Leeson is at the GlaxoSmithKline Medicines Research Centre, Stevenage SG1 2NY, UK.