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This technical article from the medical journal The American family Physician August 1, 2007 Vol. 76 No. 3 describes the [DEF]pharmacokinetics[/DEF] of how some medications have the potential for drug interactions. Below is the introduction to the article as well as an excerpt which discusses how adverse side effects can occur.

The complete article can be read and saved from the pdf file attached to the this posting.

The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects

[DEF]Cytochrome[/DEF] P450 [DEF]enzymes[/DEF] are essential for the metabolism of many medications. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6.

Genetic variability (polymorphism) in these enzymes may influence a patient's response to commonly prescribed drug classes, including beta blockers and antidepressants. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures.

Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the cytochrome P450 enzymes. Knowledge of the most important drugs metabolized by cytochrome P450 enzymes, as well as the most potent inhibiting and inducing drugs, can help minimize the possibility of adverse drug reactions and interactions.

Although [DEF]genotype[/DEF] tests can determine if a patient has a specific enzyme polymorphism, it has not been determined if routine use of these tests will improve outcomes. (Am Fam Physician 2007;76:391-6.)

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Adverse Drug Effects
Standard drug doses may cause adverse effects related to elevated drug serum levels if a person is a poor metabolizer or has a CYP450 enzyme inhibitor added to therapy.5,29 Adverse effects are more likely to occur if a drug has a narrow safety range or is dependent on only one enzyme for metabolism.

Consider the following scenario: A 35-year-old white woman with panic disorder was treated with paroxetine (Paxil). She developed unrelated hypertension, for which the physician prescribed 50 mg daily of extended-release metoprolol (Toprol XL). The patient became symptomatically orthostatic after a few days and presented to the emergency department. In this example, metoprolol, which is metabolized solely by CYP2D6, was present in higher serum levels in the patient because of the use of paroxetine.

Peak serum levels of simvastatin (Zocor), which is metabolized solely by CYP3A4, also can increase by many times in patients who are poor metabolizers or with the addition of a potent inhibitor (e.g., verapamil [Calan], nefazodone [Serzone; brand not available in the United States]), increasing the risk of myopathy and rhabdomyolysis at usual doses.30

Some drugs, such as tramadol or losartan (Cozaar), are not therapeutic until they are metabolized to active compounds. These medications, known as prodrugs, may cause an exaggerated therapeutic effect or adverse effect when a CYP450 inducer is added. Conversely, if a CYP450 inhibitor is combined with a prodrug, or a person is a poor metabolizer of a prodrug, therapeutic failure is likely to result because of little or no production of the active drug.31,32

Related Editorial: Is Genetic Testing for Cytochrome P450 Polymorphisms Ready for Implementation?

For more information on this topic, please see This Psychlinks Posting


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