Drug metabolism

Metabolism is the process by which drugs are chemically altered from a lipid-soluble form suitable for absorption and distribution to a more water-soluble form that is necessary for excretion. Some drugs, known as ‘prodrugs’, are inactive in the form in which they are administered, but are converted to an active metabolite in vivo.

Phase I metabolism involves oxidation, reduction or hydrolysis to make drug molecules suitable for phase II reactions or for excretion. Oxidation is by far the most common form of phase I reaction and chiefly involves members of the cytochrome P450 family of membrane-bound enzymes in the endoplasmic reticulum of hepatocytes.

Phase II metabolism involves combining phase I metabolites with an endogenous substrate to form an inactive conjugate that is much more water-soluble. Reactions include glucuronidation, sulphation, acetylation, methylation and conjugation with glutathione. This is necessary to enable renal excretion, because lipid-soluble metabolites will simply diffuse back into the body after glomerular filtration .

Drug excretion

 Excretion is the process by which drugs and their metabolites are removed from the body.

Renal excretion is the usual route of elimination for drugs or their metabolites that are of low molecular weight and sufficiently water-soluble to avoid reabsorption from the renal tubule. Drugs bound to plasma proteins are not filtered by the glomeruli. The pH of the urine is more acidic than that of plasma, so that weakly acidic drugs (e.g. salicylates) become un-ionised and tend to be reabsorbed. Alkalination of the urine can has ten excretion (e.g. after a salicylate overdose). For some drugs, active secretion into the proximal tubule lumen, rather than glomerular filtration, is the predominant mechanism of excretion (e.g. methotrexate, penicillins).

Faecal excretion is the predominant route of elimination for drugs with high molecular weight, including those that are excreted in the bile after conjugation with glucuronide in the liver and any drugs that are not absorbed after enteral administration. Molecules of drug or metabolite that are excreted in the bile enter the small intestine where they may, if they are sufficiently lipid-soluble, be reabsorbed through the gut wall and return to the liver via the portal vein (see Fig. 1). This recycling between the liver, bile, gut and portal vein is known as ‘enterohepatic circulation’ and can significantly prolong the residence of drugs in the body (e.g. digoxin, morphine, levothyroxine).

Fig1. Pharmacokinetics summary. Most drugs are taken orally, are absorbed from the intestinal lumen and enter the portal venous system to be conveyed to the liver, where they may be subject to first-pass metabolism and/or excretion in bile. Active drugs then enter the systemic circulation, from which they may diffuse (or sometimes be actively transported) in and out of the interstitial and intracellular fluid compartments. Drug that remains in circulating plasma is subject to liver metabolism and renal excretion. Drugs excreted in bile may be reabsorbed, creating an enterohepatic circulation. First-pass metabolism in the liver is avoided if drugs are administered via the buccal or rectal mucosa, or parenterally (e.g. by intravenous injection).

Elimination kinetics

The net removal of drug from the circulation results from a combination of drug metabolism and excretion and is usually described as ‘clearance’, i.e. the volume of plasma that is completely cleared of drug per unit time.

For most drugs, elimination is a high-capacity process that does not become saturated, even at high dosage. The rate of elimination is, there fore, directly proportional to the drug concentration because of the ‘law of mass action’, whereby higher drug concentrations will drive faster metabolic reactions and support higher renal filtration rates. This results in ‘first-order’ kinetics, when a constant fraction of the drug remaining in the circulation is eliminated in a given time and the decline in concentration over time is exponential (see Fig. 2). This elimination can be described by the drug’s half-life (t 1/2 ), i.e. the time taken for the plasma drug concentration to halve, which remains constant throughout the period of drug elimination. The significance of this phenomenon for prescribers is that the effect of increasing doses on plasma concentration is predictable – a doubled dose leads to a doubled concentration at al time points.

Fig2. Drug concentrations in plasma following single and multiple drug dosing. In this example of first-order kinetics following a single intravenous dose, the time period required for the plasma drug concentration to halve (half-life, t,,) remains constant throughout the elimination process.

For a few drugs in common use (e.g. phenytoin, alcohol), elimination capacity is exceeded (saturated) within the usual dose range. This is called ‘zero-order’ kinetics. Its significance for prescribers is that, if the rate of administration exceeds the maximum rate of elimination, the drug will accumulate progressively, leading to serious toxicity.

مواضيع ذات صلة

Drug distribution

Dose–response relationships

السلفوناميدات

Antibiotic Resistance

البنسيلينات Penicillins

المضادات الحيوية المثبطة لصناعة الجدار الخلوي

Aminoglycosides and spectinomycin

β-lactam antibiotics

مضادّات الببتيد الدهنية وغليكو ببتيد الدهنية الحيوية

التجميع الإنزيمي للبتيد السباعي للفانكوميسين وكلوروإرموميسين (chloroermomycin)

تعديلات السلسلة الجانبية في مضادّات الكيفالوسبورين: أجيال متعددة

Drug targets and mechanisms of action