A Guide To Drug-Drug Interactions In Podiatry

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Understanding How Drugs Affect Enzymes

The major group of enzymes in the liver responsible for metabolizing drugs can be isolated in a sub-cellular fraction termed the “microsomes.” Cytochrome P450 is a “superfamily” of enzymes that are the terminal oxidases of this oxidation system. “Cytochrome” means colored cells. These enzymes contain iron and give the liver its red color. The name “P450” comes from the observation that the enzyme absorbs a very characteristic wavelength (450 nm) of ultraviolet light when it is exposed to carbon monoxide.

These enzymes are named according to families that are defined by the similarity of their amino acid sequence. These P450 iso-enzymes are denoted with the following numbers and letters: CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.10-12 More than 50 percent of currently used medications that are metabolized undergo CYP3A4 metabolism.

The CYP3A subfamily is of particular interest because it is responsible for the metabolism of a large number of clinically important drugs in humans.11 The CYP3A4 isozyme accounts for over 25 percent of hepatic CYP450 content and is responsible for over half of all CYP450-mediated drug metabolisms. About 14 percent of the adult liver contains a substantial proportion of CYP3A5. However, it is proportionally more important in intestinal tissue and is the primary CYP3A enzyme in the kidney.11,12

A drug that is metabolized by a particular isoenzyme is a substrate for that enzyme. A drug can be a substrate for several different isoenzymes or an active metabolite can be a substrate for a different isoenzyme to the parent drug. These pharmacokinetic drug interactions affecting metabolism are often clinically significant and can involve induction (increased metabolism) or inhibition (reduced metabolism) of enzymes. Competition between two drugs for cytochrome P450 isozymes will occur. This competition may result in one drug interfering with the metabolism of another drug.

Medications metabolized by CYP3A4 or CYP2C9 are particularly susceptible to enzyme induction. Drugs known as “enzyme inducers” are capable of increasing the activity of drug metabolizing enzymes, resulting in a decrease in the effect of certain other drugs. For therapeutic agents that undergo extensive first-pass metabolism by CYP3A in the gut wall and liver, the reduction in serum concentrations of object drugs by enzyme inducers (precipitant drugs) can be profound. Enzyme inducers can increase the formation of toxic metabolites and increase the risk of hepatotoxicity as well as damage to other organs.

Robert G. Smith, DPM, MSc, RPh, CPed

   Precipitant drugs that act as binding agents, such as cholestyramine (Questran, Bristol-Myers Squibb) and colestipol (Colestid, Pfizer), can impair the bioavailability of object drugs. Thus, an impairment of the bioavailability of the object drug results in a reduction of therapeutic effect of the object drug. The amount of a medication that is absorbed from the gut may be increased or decreased by drugs that increase stomach pH. Interactions affecting the rate of absorption are generally insignificant unless the patient must achieve therapeutic plasma levels quickly as in the case of analgesics. Conversely, interactions affecting the extent of absorption may affect the efficacy of a drug.

   Once absorbed, most drugs bind to plasma proteins that are specific for some aspect or structural feature of the drug. The term, volume of distribution, commonly describes the extent of drug distribution to tissues relative to the plasma volume.

   Drug metabolism refers to enzyme-mediated structured modification to a drug that changes its biological activity and/or water solubility. Drug metabolism occurs as a result of enzymatic reactions on the medications that result in metabolites that may be active or rendered inactive. The gastrointestinal wall, lungs, liver and blood possess enzymes that metabolize drugs.6-8

   Metabolism via the smooth endoplasmic reticulum of the liver is the first step in the elimination of many drugs.6,8 Drug metabolism by the liver occurs through one or both biotransformation reactions that are classified as either Phase I or Phase II reactions.7 Phase I reactions modify the drug by using oxidation, hydrolysis and reduction. These modifying reactions create a more polar and highly water-soluble drug molecule for elimination by the kidneys.

   Phase II reactions modify the drug pharmacologically to an inactive form via conjugation resulting in glucuronides, acetates and sulfates. This occurs via the formation of a covalent linkage between a functional group appearing on the parent drug as a result of phase I metabolism and endogenously derived glucuronic acid, sulfate, glutathione, amino acids or acetate.6,9 The kidneys may now eliminate this new drug metabolite.

   Some important preventable drug interactions are due to their effects on drug metabolizing enzymes, resulting in either reduced activity of the enzyme or increased activity of the enzyme referred to as enzyme induction (see “Understanding How Drugs Affect Enzymes” at the right).

   Metabolism and elimination are responsible either separately or together for drug inactivation. Without these two pharmacokinetic functions, drugs would continuously circulate through our bodies, interacting with various body receptors and interrupting important physiological processes.13 Drugs are either eliminated directly or converted into metabolites that are subsequently excreted.

   Removal of a drug from the body may occur by a number of routes, the most important being through the kidney into the urine. Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. Drugs that have the same active transport mechanism can compete for excretion in the kidney tubules. Active secretion into the renal tubules is an important route of elimination for some drugs. Other routes of elimination for drugs from the body include sweat, tears, breast milk or expired air. Some drugs are excreted in the bile as water-soluble conjugates. Bacteria in the gut can break down these conjugates to liberate the free drug, which can then be reabsorbed.

   Pharmacodynamic interactions are due to competition at receptor sites or activity of the interacting drugs on the same physiological system. There is no change in plasma concentrations of interacting drugs. When patients concurrently take medications with similar pharmacodynamic effects, this may result in an additive pharmacologic excessive response and possible drug toxicity. Conversely, drugs with opposing pharmacodynamic effects may reduce the response to one or both drugs. The pharmacodynamic consequences precipitated by drug-drug interactions may or may not closely follow pharmacokinetic drug changes.

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