Metabolism

Metabolism (of a drug) refers to the enzymatic conversion of a drug to a metabolite, usually (but not always) to make the drug easier to excrete from the body. Metabolism occurs in various tissues and organs throughout the body but the liver is the most important organ responsible for metabolism. The intrinsic clearance for a drug is a value that indicates how rapidly and efficiently drugs are metabolised by (liver) enzymes. A drug which is rapidly metabolised has a high intrinsic clearance; such a drug would be expected to have low oral bioavailability and high hepatic clearance. Drugs that are highly lipid soluble are usually cleared by hepatic metabolism because they would be reabsorbed extensively from the kidney tubules and collecting duct, resulting in low or negligible renal clearance.

There are two major groups of processes that contribute to the metabolism of a drug; phase I and phase II reactions. Phase I metabolism is a functionalisation reaction, whereby a functional group is either introduced into a drug structure, or a pre-existing group is revealed or exposed through, for example, a dealkylation reaction. Oxidation reactions catalysed by cytochrome P450 (CYP) enzymes are the most commonly-occurring functionalisation reactions. Phase I metabolites may themselves have lower lipid solubility than the parent drug, facilitating renal elimination, or they may undergo further metabolism, via a phase II conjugation reaction, most commonly glucuronidation or sulfation, creating a large, more water-soluble metabolite that is transported out of the hepatocyte into the bile or the bloodstream. Drugs that already possess a functional group suitable for conjugation may bypass the phase I step and proceed directly to phase II. A common example is the direct conjugation of acetaminophen, which is then actively transported out of the hepatocyte into both the blood and the bile. Both acetaminophen glucuronide and acetaminophen sulphate are found in blood and urine after administration of the drug, with lower amounts of the conjugates detectable in the faeces.