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

   If alternative agents are not appropriate, then one should monitor the patient for evidence of myopathy (muscle pain or weakness) and myoglobinuria (dark urine). Temporarily stopping simvastatin/lovastatin during the short-term itraconazole therapy is a reasonable alternative as long as patients keep their primary care providers informed of the drug regimen. Alternative statin agents like fluvastatin (Lescol, Novartis), rosuvastatin (Crestor, AstraZeneca) or even pravastatin (Pravachol, Bristol-Myers Squibb) may prove beneficial in patients who need long-term therapy of itraconazole.

   All “azoles” inhibit the CYP3A4 isoenzyme.16 Yu and colleagues reported the potential fluconazole drug interactions were very frequent among hospitalized patients on systemic azole antifungal therapy, but they had few apparent clinical consequences.17 The authors reported that among the 4,185 admissions who took azole agents (fluconazole, itraconazole or ketoconazole), 2,941 (70.3 percent) admissions experienced potential azole–drug interactions. This included 2,716 (92.3 percent) patients who experienced fluconazole interactions.

   The most frequent interactions with potential moderate to major severity were co-administration of fluconazole with prednisone (25.3 percent), midazolam (Dormicum, Roche) (17.5 percent), warfarin (14.7 percent), methylprednisolone (Medrol, Pfizer) (14.1 percent), cyclosporine (Gengraf, Abbott Laboratories) (10.7 percent) and nifedipine (Adalat, Bayer HealthCare) (10.1 percent).17 Fluconazole causes an increase of phenobarbital (Solfoton) and phenytoin (Dilantin, Pfizer) levels in the blood when patients take it concurrently with these anti-seizure agents.18

   Itraconazole appears to increase the bioavailability of digoxin (Lanoxin, GlaxoSmithKline) and/or reduce the renal and non-renal clearance of digoxin by inhibiting P-glycoprotein (PGP). Digoxin toxicity may occur when one uses it in combination with itraconazole.19 P-glycoprotein is an efflux transporter found in the small intestine, kidney, liver and brain. To manage this interaction, the preferred management strategy is to use an alternative antifungal that does not inhibit P-glycoprotein.

   Digoxin toxicity may occur when one uses it in combination with clarithromycin (Biaxin, Abbott Laboratories). Clarithromycin, a macrolide, enhances the absorption of digoxin and/or reduces its elimination by inhibiting PGP transport of digoxin.20 To manage this interaction, the preferred management strategy is to use an alternative antibiotic, preferably an anti-infective that does not inhibit PGP.

   Warfarin is an anticoagulant racemic mixture of S- and R-warfarin enantiomers. The metabolism of these enantiomers is by different CYPs. S-warfarin is primarily metabolized by CYP2C9 and R-warfarin is metabolized by CYP1A2, CYP2C19 and CYP3A4. Fluconazole causes a dose-related inhibition of the metabolism by CYP2C9 and increases warfarin concentration and bleeding risk.21

   Monitor carefully for an altered warfarin response if the patient starts on an interacting “azole antifungal,” stops taking it or changes dosage. Inhibition of warfarin metabolism by CYPC9 and resulting bleeding risk can occur with sulfamethoxazole/trimethoprim (Bactrim, Roche) and metronidazole (Flagyl, Pfizer).21 Researchers have reported that quinolones and macrolides increase the anticoagulant effects of warfarin.21 Oral penicillin, amoxicillin (Amoxil, GlaxoSmithKline), ampicillin, oral cephalosporins and penicillins have not been shown to interact with warfarin. These agents are considered preferred alternatives. In those cases when alternatives are not appropriate, carefully monitor the international normalized ratio (INR) and check for signs of bleeding.

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