Optimising drug properties to ensure good oral bioavailability

Requirements for a ‘good drug’ * Effective target interactions * Suitable shape/size/chemical composition * Good chemical stability * Favourable hydrophobic/hydrophilic characteristics (log P = 1-3) * Aqueous solubility * Oral bioavailability * Pharmacokinetics Compounds with the best target binding interactions may fail as drugs due to poor in vivo properties or metabolic reactions within the body.

• A drug’s lipophilicity affects its absorption, distribution and elimination. • Drugs must be lipophilic to cross cell membranes, but… • if they are too lipophilic they may be deposited in fatty tissue. • Polar functional groups are needed to bind to receptors/enzymes (H-bonds). The octanol-water partition coefficient (P) is a physicochemical parameter that measures drug lipophilicity

• Equal volumes of water and octanol • Known mass of drug • Mix thoroughly • Allow two phases to separate • Measure the concentration of drug in each phase • log P values can be predicted in silico • Values obtained computationally are known as clog P • calculated log P

Qualitative rule of thumb, often used in pharmaceutical science because it works very well! * Considers physiochemical properties of a drug candidate in terms of potential bioavailability. * The rule predicts that good oral bioavailability (i.e., suitable drug concentration in circulation following oral administration) is likely when: * Molecular weight ≤ 500 * log P ≤ 5 * No more than 5 hydrogen bond donors * No more than 10 hydrogen bond acceptors * All units are multiples of five Optimum drug log P is usually in the range 1-3 * log P is carefully considered in drug design to ensure optimum lipophilicity if the log p is to high it can be injected by IV straight into body

Nota bene: the Rule of Five is strictly qualitative Most drugs (>80%) satisfy the Rule-of-5 Those that do not, however, are not necessarily poor drugs Bioavailability problems can be solved by formulation or by an alternative route of delivery, or a drug may be chemically modified to alter its polarity and log P