Am Fam Physician. 1998 Oct 1;58(5):1070.
to the editor: In the article written by Drs. Cupp and Tracy1 on cytochrome P450 enzymes, the first illustrative case describes a patient who developed dry mouth, dizziness and prolongation of the prothrombin time after paroxetine and then fluoxetine were added to her medication regimen, which included amitriptyline and warfarin.
In Table 1, paroxetine is listed as an inhibitor and amitriptyline is listed as a substrate.1 Warfarin is listed as a substrate in Tables 3 and 41; however, neither of these tables lists paroxetine or fluoxetine as a potential inhibitor.
Presumably the patient's dry mouth and dizziness were related to a drug interaction between paroxetine and amitriptyline; however, what was the reason for the prolonged International Normalized Ratio (INR)?
1. Johns Cupp M, Tracy TS. Cytochrome P450: new nomenclature and clinical implications. Am Fam Physician. 1998;57:107–16.
in reply: We appreciate Dr. Liu's question concerning the cause of the prolonged International Normalized Ratio (INR) in the patient described in the illustrative case.A section of the text that would have explained this drug interaction was omitted from the final version of the manuscript at the suggestion of a reviewer who thought it would be “confusing to clinicians.” However, we feel, as does Dr. Liu, that this interaction warrants an explanation.
Warfarin is a racemic mixture of R-warfarin and S-warfarin, which differ in potency and metabolic pathways.1 R-warfarin is a less potent anticoagulant than is S-warfarin,1 which is metabolized by CYP2C9.2 CYP1A2 and CYP3A are the enzymes responsible for the metabolism of the less potent R-warfarin.
In the case presented in our article, the addition of fluoxetine, a CYP3A inhibitor, to the medication regimen of the patient was the likely cause of the increase in the INR. There is also limited information that suggests fluoxetine is a CYP2C9 inhibitor3; thus, it is an inhibitor of the more potent S-enantmer.
Despite case reports of a drug interaction between fluoxetine and warfarin,4 results of a pharmacokinetic study5 did not support a clinically significant interaction. Physicians may or may not see a change in the INR of a patient when a CYP3A inhibitor is added to warfarin therapy. The propensity for a clinically significant interaction might be influenced by interindividual activity of CYP3A, or by other medications taken by the patient that inhibit other warfarin metabolic pathways.
1. Porter RS, Sawyer WT. Warfarin. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied pharmacokinetics: principles of therapeutic drug monitoring. 3d ed. Vancouver, Wash.: Applied Therapeutics, 1992:31.1–46.
2. Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther. 1997;73:67–74.
3. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet. 1997;32 (Suppl 1):1–21.
4. Prozac (fluoxetine) prescribing information. Indianapolis, Ind.: Eli Lilly and Co., 1997.
5. Rowe H, Carmichael R, Lemberger L. The effect of fluoxetine on warfarin metabolism in the rat and man. Life Sci. 1978;23:807–11.
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