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.

Author(s): 
Robert G. Smith, DPM, MSc, RPh, CPed

   Another drug-drug management option is to space the dosing times of each interacting drug to avoid the interaction. This option allows for the object drug to be absorbed into the circulation before the precipitant drug. Always provide information on patient risk factors that increase the chance for an adverse outcome to the patient or patient caretaker so the patient avoids the adverse effects of drug-drug interactions. Computerized drug interaction screening systems are helpful tools that the podiatric physician may use but improvement in these systems is necessary.

In Conclusion

One can predict the potential for important drug interactions based on the properties of the causative agent and the interacting agent. The majority of drug-drug interactions have known factors grounded in science. However, many healthcare providers rely solely on inductive reasoning based on personal clinical experience as a guide to the clinical importance of most drug-drug interactions.

   Published clinical evidence does exist for many of the reported drug-drug interactions that cause serious adverse reactions. Therefore, podiatric physicians should consider the results of published literature as well as their own clinical experience when making decisions on the potential for drug interactions in their patient population.

   Dr. Smith is in private practice at Shoe String Podiatry in Ormond Beach, Fla.

References

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8. Hansten PD, Horn JR. Drug interaction mechanisms: enzyme induction. In Hansten and Horn’s Drug Interactions Analysis and Management. Facts and Comparison, St. Louis, MO, 2003, pp. 1-15.

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10. Nelson DR, Koymans L, Kamataki T et al. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics. 1996; 6(1):1-42.
11. Streetman DS. Metabolic differences and pharmacogenetics: Implications for anesthesia. Anesthesia Today. 2004; 14(3):12-20.

12. Koch I, Weil R, Woldold R, et al. Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA. Drug Metab Dispo. 2002; 30(10):1008-1114.

13. Soldin OP, Mattison DR. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinetics. 2009; 48(3):143-157.

14. Horn JR, Hansten PD. The ignorance of certainty-“facts” sometimes aren’t. Pharmacy Times, 2005. Available at www.hanstenandhorn.com/hh-article09-05.pdf. Accessed May 1, 2011.

15. McInnes GT, Brodie MJ. Drug interactions that matter. A critical reappraisal. Drugs. 1988; 36(1):83-110.

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