Читать книгу Clinical Pharmacology and Therapeutics - Группа авторов - Страница 28

Drugs are eliminated from the body by two principal mechanisms: (i) liver metabolism and (ii) renal excretion. Drugs that are already water‐soluble are generally excreted unchanged by the kidney. Lipid‐soluble drugs are not easily excreted by the kidney because, following glomerular filtration, they are largely reabsorbed from the proximal tubule. The first step in the elimination of such lipid‐soluble drugs is metabolism to more polar (water‐soluble) compounds. This is achieved mainly in the liver, but can also occur in the gut and may contribute to first‐pass elimination. Metabolism generally occurs in two phases:

 Phase 1 – Mainly oxidation, but also reduction or hydrolysis to a more polar compound:Oxidation can occur in various ways at carbon, nitrogen or sulphur atoms and N‐ and O‐dealkylation. These reactions are catalysed by the cytochrome P450‐dependent system of the endoplasmic reticulum. Knowledge of P450, which exists as a superfamily of similar enzymes (isoforms), has increased greatly recently and is divided into a number of families and subfamilies. Although numerous P450 isoforms are present in human tissue, only a few of these have a major role in the metabolism of drugs. These enzymes, which display distinct but overlapping substrate specificity, include CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Induction or inhibition of one or more of these enzymes may form the basis of clinically relevant drug interactions. Phase 1 metabolites usually have only minor structural differences from the parent drug, but may exhibit totally different pharmacological actions. For example, the metabolism of azathioprine produces the powerful antimetabolite 6‐mercaptopurine.

 Phase 2 – Conjugation usually by glucoronidation or sulphation to make the compound more polar: This involves the addition of small endogenous molecules to the parent drug, or to its Phase 1 metabolite, and almost always lead to abolition of pharmacological activity. Multiple forms of conjugating enzymes are also known to exist, although these have not been investigated to the same extent as the P450 system.