Anafranil

Most of us have become acquainted with the cytochrome P450 (or just P450) enzyme system, which is the metabolic pathway for a significant number of psychotropic drugs. This drug-metabolizing system was once referred to as the hepatic microsomal enzyme system (Lehne, 2001), but more precise study has refined our understanding and resulted in a more descriptive designation.

The P450 enzymes are oxidase systems, and more than 40 P450 enzyme subtypes have been identified in humans (Cozza & Armstrong, 2001). Six of these enzymes are responsible for 90% of human drug oxidation: 1A2, 3A4, 2C9, 2C19, 2D6, and 2E1 (Cozza & Armstrong; Guengerich, 1997). The P450 enzymes are also responsible for many if not most of the drug-drug interactions that occur (Cozza & Armstrong). Drug-drug interactions cause serious complications to a patient's health, can be deadly, and are largely preventable.

A less common yet significant interaction occurs between drugs and certain foods. For example, mixing monoamine oxidase inhibitors (MAOIs) with foods containing tyramine can lead to a deadly hypertensive crisis; combining warfarin (Coumadin) with vitamin K-containing foods (e.g., green, leafy vegetables) promotes clotting-factor synthesis; and eating foods containing vitamin B6 while undergoing levodopa therapy results in increased metabolism of levodopa and its reduced effectiveness (Menke, 1998). Grapefruit juice also causes important food-drug interactions.

Grapefruit juice inhibits two of the six major P450 enyzmes---the 3A4 enzyme and, to a lesser extent, 1A2. The specific components of grapefruit juice thought to inhibit 3A4 are psoralen derivatives, the flavonoid derivatives naringenin and naringin, and several other substances (Fuhr, 1998; Fuhr & Kummert, 1995; Fukuda, Guo, Ohashi, Yoshikawa, & Yamazoe, 2000; Malhotra, Bailey, Paine, & Watkins, 2001). Singly, none of the constituents seems profoundly inhibitory, which suggests a complex synergy may be responsible for inhibition of 3A4 and 1A2. The enzyme 3A4 is located in the liver (about 30% of this enzyme), but the majority is found in the gut wall (Bailey, Malcolm, Arnold, & Spence, 1998; Cozza & Armstrong, 2001). More than 100 drugs are metabolized by this enzyme, so any agent that would inhibit 3A4 has the potential to elevate serum levels of those drugs. Table 1 lists some of the categories of drugs metabolized by 3A4.

Not all drugs in the categories listed in Table 1 are affected by grapefruit juice. Grapefruit juice has its inhibiting effect on gut wall-3A4 enzymes, hence drugs primarily metabolized by liver-3A4 enzymes are not likely to be affected by grapefruit juice (Fuhr, 1998; Menke, 1998). Following are selected examples of psychotropic agents known to have increased bioavailability when coadministered with grapefruit juice.

Anxiolytic Agents

Benzodiazepines. There have been contradictory reports on the interaction between grapefruit juice and benzodiazepines. Ozdemir, Aktan, Boydag, Cingi, and Musmul (1998) reported serum levels of diazepam (Valium) increased threefold when given with grapefruit juice. Other studies suggest increases in blood levels of triazolam (Halcion) and midazolam (Versed) when given with this juice (Fuhr, 1998; Hukkinen, Varhe, Olkkola, & Neuvonen, 1995). Kupferschmidt, Ha, Ziegler, Meier, and Krahenbuhl (1995) gave subjects oral or IV midazolam with water or grapefruit juice. Only those drinking grapefruit juice and receiving the drug orally had increased blood levels (-50%). The fact that IV midazolam did not increase in serum concentrations conforms with the information presented above that grapefruit juice only inhibits gut wall 3A4. Of course, IV midazolam would not experience a first-pass reduction. Grapefruit juice does not seem to affect alprazolam levels, and this may be related to its greater bioavailability and subsequent liver metabolism.

Buspirone. Buspirone (BuSpar) is a nonbenzodiazepine antianxiety drug with extensive first pass metabolism by P450-3A4. As little as 1% of buspirone reaches systemic circulation. When coadministered with "double-strength" grapefruit juice, buspirone has a concentration that is quadrupled (Lilja, Kivisto, Backman, Lamberg, & Neuvonen, 1998). Such dramatic increases could result in toxic levels of buspirone, leading to central nervous system effects. In such situations, advantages that buspirone has over benzodiazepines are compromised.

Antidepressants

Sertraline. Sertraline (Zoloft) is metabolized by P4503A4 and undergoes extensive first-pass metabolism (Keltner & Folks, 2001). One study reported a 50% increase in sertraline bioavailability when given with grapefruit juice (Lee, Chan, Harralson, Buffum, & Bui, 1999).

Tricylic antidepressants. Tricyclic antidepressants (TCAs) are metabolized by both 3A4 and 1A2. Amitriptyline (Elavil) and clomipramine (Anafranil), when given with grapefruit juice, have increased bioavailability (Vandel et al., 1999). Oesterheld and Kallepalli (1997) found that co-administration of grapefruit juice and clomimpramine increased clomipramine levels. Interestingly, the increase had a therapeutic effect on two children with obsessive compulsive disorder. Since TCAs are known to have a narrow therapeutic index, these are potentially important interactions.

Anticonvulsants

Carbamazepine. Carbamazepine (Tegretol) is an anticonvulsant often used in psychiatry for treatment of bipolar disorder and bipolar depression Recent research indicates mixing grapefruit juice and carbamazepine leads to a 40% increase in serum bioavailability of the anticonvulsant (Garg, Kumar, Bhargava, & Prabhakar, 1998). Since carbamazepine also has a narrow therapeutic index, this specific combination should be avoided to prevent a toxic state.

Condusion

Prescribing, administering, monitoring, and taking psychotropic drugs are serious endeavors. Knowledge about these agents is increasing rapidly-so rapidly that most of us cannot keep up. This article highlights one more potentially serious variable in the medication management of psychiatric patients. For your patients who are grapefruit juice lovers, this article is not good news. Obviously, more research needs to be conducted in this area. In the meantime, it is probably wise to recommend orange juice to these patients.

References

Bailey, D.G., MalcoLm, J., Arnold, O., & Spence, J.D. (1998). Grapefruit juice-drug interactions. British Journal of Clinical Pharmacology, 46, 101-110.

Cozza, K.L., & Armstrong, S.C. (2001). The cytochrome P450 system. Washington, DC: American Psychiatric Press.

Fuhr, U. (1998). Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance. Drug Safety, 45, 355-359.

Fuhr, U., & Kummert, A.L. (1995). The fate of naringin in humans: A key to grapefruit juice-drug interactions? Clinical Pharmacology and Therapeutics, 58, 365-373.

Fukuda, K., Guo, L., Ohasi, N., Yoshikawa, M., & Yamazoe, Y. (2000). Amounts and variation in grapefruit juice of the main components causing grapefruit-drug interactions. Journal of Chromatography. Biomedical Sciences and Applications, 741, 195-203.

Garg, S.K., Kumar, N., Bhargava, V.K., & Prabhakar, S.K. (1998). Effects of grapefruit juice on carbamazepine bioavailability in patients with epilepsy. Clinical Pharmacology and Therapeutics, 64, 286-288.

Guengerich, F.P. (1997). Role of cytochrome P450 in drug-drug interactions. Advances in Pharmacology, 43, 7-35.

Hukkinen, S.K., Varhe, A., Olkkola, KT., & Neuvonen, PJ. (1995). Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice. Clinical Pharmacology and Therapeutics, 58,127-131.

Keltner, N.L., & Folks, D.G. (2001). Psychotropic drugs Ord ed.). St. Louis: Mosby.

Kupferschmidt, H.H., Ha, H.R., Ziegler, W.H., Meier, PJ., & Krahenbuhl, S. (1995). Interaction between grapefruit juice and midazolam in humans. Clinical Pharmacology and Therapeutics, 58,20-28.

Lee, AJ., Chan, W.K., Harralson, A.F., Buffum, J., & Bui, B.C. (1999). The effects of grapefruit juice on sertraline metabolism: An in vivo study. Clinical Therapeutics, 22,1890-1899.

Lehne, RA. (2001). Pharmacology for nursing care. Philadelphia: Saunders. Lilja, JJ., Kivisto, KT., Backman, J.T., Lamberg, T.S, & Neuvonen, P.J. (1998). Grapefruit juice substantially increases plasma concentrations of buspirone. Clinical Pharmacology and Therapeutics, 64, 655-660.

Malhotra, S., Bailey, D.G., Paine, M.F., & Watkins, P.B. (2001). Seville orange juice-felodipine interaction: Comparison with dilute grapefruit juice involvement of furocoumarins. Clinical Pharmacology and Therapeutics, 69,14-23.

Menke, J. (1998). Grapefruit juice: The untold story. South Dakota Medical Journal, 51, 421-422.

Oesterheld, J., & Kallepalli, B.R. (1997). Grapefruit juice and clomipramine: Shifting metabolic ratios. Journal of Clinical Psychopharmacology, 17, 62-63.

Ozdemir, M., Aktan, Y., Boydag, B.S., Cingi, M.I., & Musmul, A. (1998). Interaction between grapefruit juice and diazepam in humans. European Journal of Metabolism and Pharmacokinetics, 23, 55-59.

Vandel, P., Regina, W., Reix, I., Vande, S., Sechter, D., & Bizouard, P. (1999). Grapefruit juice as a contraindication? An approach in psychiatry. Encephale, 25, 67-71.

Search terms: Anticonvulsants, antidepressants, anxiolytics, drug interactions

Norman L. Keltner, EdD, RN, and Ifeoma Opara, BSN, RN

Norman L. Keltner, EdD, RN

Professor, University of Alabama, Birmingham, AL

Ifeoma Opara, BSN, RN

Staff Nurse, Brookwood Hospital, Birmingham, AL

Author contact: keltner@son.uab.edu, with a copy to the Editor: mary77@concentric.net

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