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

   A person’s genetic makeup can alter the response to a medication. Genetics affect both pharmacokinetics and pharmacodynamics. Two terms describe genetic variations in drug metabolism. Pharmacogenomics applies to the entire spectrum of genes. The focus of pharmacogenomics is on individualized drug and dosage for a specific disease. When it comes to pharmacogenetics, the focus is on metabolizing enzymes and and how they are transported. Pharmacogenomics is the broader application of genomic technologies to new drug discovery and further characterization of older drugs. Pharmacogenetics is generally regarded as the study or clinical testing of genetic variation, which gives rise to different responses to drugs.

What The Recent Research Reveals About Drug-Drug Interactions

The scientific field of drug-drug interactions is relatively new. Forty years ago, the first major symposium on drug interactions took place in Britain.14 McInnes and Brodie advise clinicians to appreciate drug interactions by combining a practical knowledge of the pharmacological mechanisms involved with an awareness of the most vulnerable patients.15

   The relatively recent discoveries of cytochrome P-450 isozymes and ATP binding cassette transporters have revolutionized the field. Podiatric physicians are encouraged to have a sound knowledge of drug-induced, mechanism-based cytochrome P450 drug interactions.

   Nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics such as rifampin (Rifadin, Sanofi Aventis) are common precipitant drugs that podiatrists prescribe. Drugs with a narrow therapeutic range or low therapeutic index are more likely to be the objects for serious drug interactions. Warfarin (Coumadin, Bristol-Myers Squibb), fluoroquinolones, antiepileptic drugs, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and oral contraceptives are common object drugs.

   It is important for the podiatric physician to remember that even if a drug is not metabolized by a specific cytochrome P450 isozyme, the drug can affect the metabolism of other drugs through the cytochrome P450 pathway. However, even given all the scientific knowledge describing cytochrome P450 isozymes and the adenosine triphosphate-binding cassette transporters, the discovery of new drug interactions still occurs through careful assessment of case reports.

Key Considerations With Prescribing Azole Antifungal Agents

Many potential drug-drug interactions are clinically inconsequential. In terms of a general rule, a drug-drug interaction may be clinically relevant when the administration of another substance alters the efficacy or toxicity of a medication. Drug interactions are never straightforward because not all patients will experience the same effect to the same degree. For a ready reference source, see “A Primer On Potentially Serious Drug Interactions” (see table below).

   When a patient is stabilized on either lovastatin (Zocor, Merck) or simvastatin (Mevacor, Merck) and one adds “azole antifungal agents” to the regimen, there may be increased serum concentrations of simvastatin/lovastatin as a result. Azole antifungal agents include itraconazole (Sporanox, Janssen Pharmaceuticals), ketoconazole (Nizoral, McNeil-PPC), posaconazole (Noxafil, Schering Plough), voriconazole (Vfend, Pfizer), fluconazole (Diflucan, Pfizer). There is also a risk of myopathy/rhabdomyolysis because of the inhibition of simvastatin/lovastatin metabolism by CYP3A4.

   In these cases, the podiatric physician should consider alternative antifungal agents like terbinafine (Lamisil, Novartis) or ciclopirox nail lacquer (Penlac, Sanofi Aventis).

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