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Consultation-Liaison Psychiatry Drug–Drug Interactions Update
Consultation-Liaison Psychiatry Drug–Drug Interactions Update SCOTT C. ARMSTRONG, M.D. KELLY L. COZZA, M.D.
T
his column is now beginning its third year, and most of the columns we’ve published during the first two years have focused on the cytochrome P450 (CYP450) system. This was done deliberately because most clinically relevant known drug-drug interactions (DDI) involve the CYP450 enzymes. The column in this issue, however, opens with a review of two articles that describe P-glycoprotein. It has only been in the last five years that this transport enzyme has been recognized as contributing to various DDIs and/or alterations in drug effectiveness. Interestingly, psychotropic medications have little use of this transport enzyme; therefore, the literature that reviews P-glycoprotein tends to be found in journals not typically reviewed by psychiatrists. This is the opposite of the CYP450 system, where psychiatrists in the late 1980s led the rest of medicine with warnings about DDI problems with CYP450 enzymes. Hence, the medical literature covering CYP450 DDI is over-represented in psychiatric journals. We will watch the development of understanding about P-glycoprotein in the literature over the next few years because we suspect that more will be known about how P-glycoprotein can affect drug pharmacokinetics. The second section of this column reviews drug interactions by compounds that both inhibit and induce CYP450 enzymes. Predicting outcomes and potential problems may be tricky, and product labeling for these dual-effect drugs continues to evolve. And, finally, we close with a mention of sildenafil (Viagra) and some of the
Psychosomatics 42:3, May-June 2001
newest recommendations in light of that drug’s dependence upon CYP4503A4 for metabolism.
1. P-Glycoprotein Fromm MF: P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther 2000; 38:69–74 Huisman MT, Smit JW, Schinkel AH: Significance of Pglycoprotein for the pharmacology and clinical use of HIV protease inhibitors. AIDS 2000; 14:237–242 Verschraagen M, Koks CHW, Schellens JHM, et al: Pglycoprotein system as a determinant of drug interactions: the case of digoxinverapamil. Pharmacol Res 1999; 40:301– 306 These articles are excellent concise reviews of what is currently known about P-glycoprotein (P-gp) and its role in DDI. Fromm’s is a concise overview of P-gp, whereas the other two articles review some specific DDI issues with P-gp. P-gp is an ATP-dependent cell surface transport membrane glycoprotein. It appears to be involved in volumeregulated chloride channel activity and transport of steroid hormones. P-gp
also has a “protective” role for cells by extruding xenobiotic compounds out of the cells and into the urine, bile, and intestinal lumen. P-gp is expressed in apical membranes of cells in organs with excretory function such as the kidney, liver, and small intestine. It also is a major reason for the brain’s protective blood-brain barrier, as P-gp is located in the capillary endothelial cells of the brain. P-gp’s clinical/pharmacokinetic importance was first recognized in 1996 from its role in contributing to multidrug resistance during chemotherapy with tumors. Overexpression of P-gp by tumor cells can reduce the effectiveness of drugs that are substrates for P-gp, such as vinca alkaloids and paclitaxel. Some researchers have advocated using inhibitors of P-gp to counteract this anti-tumor drug resistance. Such potential inhibitors of P-gp include analogs of cyclosporine, which are not significant immunosuppresants in humans but could enhance the efficacy of anticancer agents. Since this early finding that P-gp can render anti-tumor drugs less effective, other important P-gp pharmacokinetic mechanisms have been recognized in the last several years. These fall under two broad categories: 1) P-gp’s role in gut absorption of medications, and 2) P-gp’s role in prevention of drug penetration into the brain. The gastrointestinal tract is not a passive “barrier” to medications. CYP4503A4 in luminal gut cells has been known to metabolize drugs before they are absorbed (part of the “first pass” mechanism of drug elimination). 269
Drug-Drug Interaction P-gp also is engaged in this mechanism to control the absorption of xenobiotic compounds, but P-gp does this by pumping the medication out of the luminal cell back into the gastrointestinal tract. It is known that most protease inhibitors, digoxin, cyclosporine, and some b-adrenergics are effluxed by P-gp. If P-gp function is inhibited or induced, this could change the absorption of these medications. For example, quinidine has been known to raise digoxin levels for many years. The mechanism involves quinidine inhibiting P-gp activity, therefore allowing digoxin to be absorbed more easily, raising levels to potential toxicity. Other drugs that raise digoxin levels because of their possible inhibition of P-gp are verapamil, propafenone, cyclosporine, itraconazole and amiodarone. With regard to verapamil, concurrent use with digoxin may cause digoxin toxicity from inhibition of P-gp at renal tubules, since renal tubules use P-gp to transport digoxin out of the cells and into the urine. Unlike CYP450 inhibition, drugs that inhibit P-gp do so noncompetitively. In contrast, rifampin has been shown to decrease digoxin levels by inducing P-gp, presumably in the gastrointestinal tract. This induction increases the P-gp transport activity, thus reducing the digoxin levels by pumping the digoxin back out into the gut. In the brain, protease inhibitor concentrations are reduced by P-gp activity in the endothelial cells of the blood-brain barrier. It has been speculated that the availability of these drugs to achieve therapeutic central nervous system (CNS) concentrations may be limited because of this mechanism and that a potential sanctuary for viral replication may exist in the brain. One wonders if inhibiting P-gp in the brain would help in increasing the effectiveness of these drugs there. The risk of 270
serious toxicity by this strategy, however, may make this a difficult task. Interestingly, most psychotropic medications are not substrates for P-gp, and therefore reach adequate CNS concentrations. This makes some intuitive sense, since psychotropics need to achieve adequate levels within the CNS to be effective, and having a transport system that prevents their absorption into the CNS would most likely eliminate any potential for a drug to work psychotropically. Clearly more study is needed to fully understand the role of P-gp. Genetic differences may exist and environmental factors may alter its function by inhibition or induction. Additionally, many other drugs may inhibit or induce P-gp, creating clinical challenges or potential opportunities. Our breadth of knowledge of these specifics of P-gp is currently in its infancy. We expect to read much more about this transport enzyme in the next few years. —SCA
2. Concurrent Inhibition and Induction Greenblatt DJ, von Moltke LL, Daily JP, et al: Extensive impairment of triazolam and alprazolam clearance by shortterm low-dose ritonavir: the clinical dilemma of concurrent inhibition and induction. J Clin Psychopharmacol 1999; 19:293–296 Greenblatt DJ, von Moltke LL, Harmatz JS, et al: Alprazolamritonavir interaction: implications for product labeling. Clin Pharmacol Ther 2000; 67:335–341
Piscitelli SC, Kress DR, Bertz RJ, et al: The effect of ritonavir on the pharmacokinetics of meperidine and normeperidine. Pharmacotherapy 2000; 20:549– 553 Ritonavir is a protease inhibitor, one of the drugs commonly found in Highly Active Antiretroviral Therapy (HAART) or the “cocktail” for the treatment of Human Immunodeficiency Virus (HIV) infections. Ritonavir is the most potent inhibitor of CYP450 enzymes of the protease inhibitors. It is, in fact, a “pan-inhibitor,” having the ability to potently and competitively inhibit many if not all of the known CYP450 enzymes. This potential to inhibit the metabolism of drugs dependent on CYP450 enzymes for metabolism has led to multiple warnings in ritonavir’s product labeling, supported by many case reports and in vitro and in vivo studies. To add to this complexity, ritonavir is also an inducer of CYP4503A4. Briefly, to review the processes of induction and inhibition: induction increases enzyme production, where an inducing drug actually “encourages” the production of more enzyme (protein synthesis), making more sites available for metabolism. Induction takes several days to weeks to reach steady state in the presence of an inducing agent, and it also takes several weeks to return to normal metabolic rates, or to a normal number of enzyme sites. Conversely, competitive inhibition is immediate and occurs only in the presence of the inhibiting agent (the drug with the lower Ki, or the higher affinity for the enzyme). Inhibition leads to a slowed metabolism of parent drugs dependent on that occupied enzyme, which may lead to toxicity (as in the case of pimozide or the triazolobenzodiazepines alprazolam, triazoPsychosomatics 42:3, May-June 2001
Drug-Drug Interaction lam, and midazolam), or ineffectiveness (as in the case of codeine, which must be metabolized at CYP4502D6 to its active morphine compound). Once an inhibiting agent is discontinued, the inhibition of that metabolic site is over quickly (depending on the inhibitors half-life) and the site is open for metabolism of other agents. Greenblatt’s group provides a thorough review of the issues of inhibition and induction by a single agent: ritonavir. The first citation above is an editorial, but it is actually a well-written, concise review of the literature concerning concomitant inhibition and induction. The authors report that ritonavir might cause toxicity of drugs dependent on the CYP450 system for metabolism in the first few days but that this competitive inhibition is eventually diminished as the drug’s ability to induce metabolism takes full effect. They state that “the net effect of ritonavir on CYP3A-mediated metabolism in vivo represents a balance of inhibition and induction which is not easily predicted” (p. 294). Alprazolam and triazolam, as mentioned above, are triazolobenodiazepines, which are dependent on CYP4503A4 for metabolism. Short-term (32 hours) in vivo study of healthy volunteers reveals that ritonavir indeed impairs metabolism of alprazolam, leading to prolongation of elimination half-life, increase in total area under the concentration curve (AUC), and reduction of clearance. Importantly, Greenblatt’s group also studied the pharmacodynamic effects of this metabolic inhibition and found that there was an increase in sedation, an increase in beta amplitude on EEG, and an impairment in performance on the Digit Symbol Substitution Test. These authors cite a 10-day study where the effects of inhibition by ritonavir were not evident, probably because ritonaPsychosomatics 42:3, May-June 2001
vir’s ability to induce the same enzyme it inhibits balanced the effects found in shorter studies. A complicating factor in determining or predicting the effects of a drug like ritonavir is that most protease inhibitors also may inhibit P-gp, adding to the drug-response variability. Piscitelli et al. performed a 10-day crossover study of ritonavir and its effects on meperidine and normeperidine in healthy volunteers. They found meperidine’s AUC to be significantly reduced, not increased (as predicted in initial product labeling, which was based on in vitro and short- term studies). They found increased concentrations of normeperidine, the neurotoxic metabolite of meperidine, which has a longer half-life and has been found to cause delirium. The reason for increased levels of normeperidine is because the induced enzyme that metabolizes meperidine is now over-metabolizing and producing more of the toxic metabolite normeperidine. They did not study pharmacodynamic effects, and they did not study pain patients with long-term use of meperidine, where a decrease in parent compound may lead to breakthrough pain or withdrawal. The “take-home” message from these three papers is that product labeling needs to reflect more clearly the time course of drug interaction effects. Potent inhibitors like ritonavir will cause immediate drug interactions that may be toxic, but longer-term use of a drug that both inhibits and induces like ritonavir may lead to loss of clinical efficacy of the co-administered drug, accumulation of toxic metabolites, or in a best-case scenario, no overall adverse effects. Caution is always warranted with drugs dependent on CYP450 metabolism with narrow therapeutic windows or with toxic metabolites. Clinical monitoring and drug level sampling would be prudent. —KLC
3. Sildenafil (Viagra)
Warrington JS, Shader RI, von Moltke LL, et al: In vitro biotransformation of sildenafil (Viagra): identification of human cytochromes and potential drug interactions. Drug Metab Dispos 2000; 28:392–397
Muirhead GJ, Wulff MB, Fielding A, et al: Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir. Br J Clin Pharmacol 2000; 50:99–107 Just a quick review of sildenafil’s metabolic sites and potential drug interactions. Warrington et al. studied sildenafil in vitro using human liver microsomes and in microsomes containing heterologously expressed human chromosomes, using the inhibitors omeprazole (CYP450-2C19), quinidine (2D6), sulfaphenazole (2C9), ketoconazole (3A4), and ritonavir (all CYP450 enzymes). The authors found that sildenafil metabolism was inhibited by ketoconazole and ritonavir. The metabolite of sildenafil, UK-103,320 was formed by 3A4, 2C9, 2C19 and 2D6, the latter two contributing just 2%. The primary metabolic site for sildenafil in vitro was 3A4 and, to a much lesser extent, 2C9. Muirhead et al. studied the effect of two protease inhibitors on sildenafil in healthy volunteers in two studies of 28 volunteers each. They found that both protease inhibitors increased the Cmax, AUC, tmax, and half-life of sildenafil and its metabolite. Ritonavir 271
Drug-Drug Interaction had a greater impact on the increases than saquinavir, and the authors conclude that this may be due to ritonavir inhibiting both 3A4 and 2C9. They noted no adverse or more pronounced effects from the interactions. They do recommend a lower starting dose of sildenafil (25 mg) in patients already taking saquinavir and not to exceed a max-
272
imum of 25 mg in a 48-hour period for patients on ritonavir. Of note, these were small studies, and these were not ill patients on multiple medications. — KLC Dr. Armstrong is Co-Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest
Grove, OR; Dr. Cozza is an HIV Psychiatrist with the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC. Address correspondence to Dr. Armstrong, Tuality Forest Grove Hospital, 1809 Maple Street, Forest Grove, OR 97116, or scott.armstrong@ tuality.org.
Psychosomatics 42:3, May-June 2001
T
his column is now beginning its third year, and most of the columns we’ve published during the first two years have focused on the cytochrome P450 (CYP450) system. This was done deliberately because most clinically relevant known drug-drug interactions (DDI) involve the CYP450 enzymes. The column in this issue, however, opens with a review of two articles that describe P-glycoprotein. It has only been in the last five years that this transport enzyme has been recognized as contributing to various DDIs and/or alterations in drug effectiveness. Interestingly, psychotropic medications have little use of this transport enzyme; therefore, the literature that reviews P-glycoprotein tends to be found in journals not typically reviewed by psychiatrists. This is the opposite of the CYP450 system, where psychiatrists in the late 1980s led the rest of medicine with warnings about DDI problems with CYP450 enzymes. Hence, the medical literature covering CYP450 DDI is over-represented in psychiatric journals. We will watch the development of understanding about P-glycoprotein in the literature over the next few years because we suspect that more will be known about how P-glycoprotein can affect drug pharmacokinetics. The second section of this column reviews drug interactions by compounds that both inhibit and induce CYP450 enzymes. Predicting outcomes and potential problems may be tricky, and product labeling for these dual-effect drugs continues to evolve. And, finally, we close with a mention of sildenafil (Viagra) and some of the
Psychosomatics 42:3, May-June 2001
newest recommendations in light of that drug’s dependence upon CYP4503A4 for metabolism.
1. P-Glycoprotein Fromm MF: P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther 2000; 38:69–74 Huisman MT, Smit JW, Schinkel AH: Significance of Pglycoprotein for the pharmacology and clinical use of HIV protease inhibitors. AIDS 2000; 14:237–242 Verschraagen M, Koks CHW, Schellens JHM, et al: Pglycoprotein system as a determinant of drug interactions: the case of digoxinverapamil. Pharmacol Res 1999; 40:301– 306 These articles are excellent concise reviews of what is currently known about P-glycoprotein (P-gp) and its role in DDI. Fromm’s is a concise overview of P-gp, whereas the other two articles review some specific DDI issues with P-gp. P-gp is an ATP-dependent cell surface transport membrane glycoprotein. It appears to be involved in volumeregulated chloride channel activity and transport of steroid hormones. P-gp
also has a “protective” role for cells by extruding xenobiotic compounds out of the cells and into the urine, bile, and intestinal lumen. P-gp is expressed in apical membranes of cells in organs with excretory function such as the kidney, liver, and small intestine. It also is a major reason for the brain’s protective blood-brain barrier, as P-gp is located in the capillary endothelial cells of the brain. P-gp’s clinical/pharmacokinetic importance was first recognized in 1996 from its role in contributing to multidrug resistance during chemotherapy with tumors. Overexpression of P-gp by tumor cells can reduce the effectiveness of drugs that are substrates for P-gp, such as vinca alkaloids and paclitaxel. Some researchers have advocated using inhibitors of P-gp to counteract this anti-tumor drug resistance. Such potential inhibitors of P-gp include analogs of cyclosporine, which are not significant immunosuppresants in humans but could enhance the efficacy of anticancer agents. Since this early finding that P-gp can render anti-tumor drugs less effective, other important P-gp pharmacokinetic mechanisms have been recognized in the last several years. These fall under two broad categories: 1) P-gp’s role in gut absorption of medications, and 2) P-gp’s role in prevention of drug penetration into the brain. The gastrointestinal tract is not a passive “barrier” to medications. CYP4503A4 in luminal gut cells has been known to metabolize drugs before they are absorbed (part of the “first pass” mechanism of drug elimination). 269
Drug-Drug Interaction P-gp also is engaged in this mechanism to control the absorption of xenobiotic compounds, but P-gp does this by pumping the medication out of the luminal cell back into the gastrointestinal tract. It is known that most protease inhibitors, digoxin, cyclosporine, and some b-adrenergics are effluxed by P-gp. If P-gp function is inhibited or induced, this could change the absorption of these medications. For example, quinidine has been known to raise digoxin levels for many years. The mechanism involves quinidine inhibiting P-gp activity, therefore allowing digoxin to be absorbed more easily, raising levels to potential toxicity. Other drugs that raise digoxin levels because of their possible inhibition of P-gp are verapamil, propafenone, cyclosporine, itraconazole and amiodarone. With regard to verapamil, concurrent use with digoxin may cause digoxin toxicity from inhibition of P-gp at renal tubules, since renal tubules use P-gp to transport digoxin out of the cells and into the urine. Unlike CYP450 inhibition, drugs that inhibit P-gp do so noncompetitively. In contrast, rifampin has been shown to decrease digoxin levels by inducing P-gp, presumably in the gastrointestinal tract. This induction increases the P-gp transport activity, thus reducing the digoxin levels by pumping the digoxin back out into the gut. In the brain, protease inhibitor concentrations are reduced by P-gp activity in the endothelial cells of the blood-brain barrier. It has been speculated that the availability of these drugs to achieve therapeutic central nervous system (CNS) concentrations may be limited because of this mechanism and that a potential sanctuary for viral replication may exist in the brain. One wonders if inhibiting P-gp in the brain would help in increasing the effectiveness of these drugs there. The risk of 270
serious toxicity by this strategy, however, may make this a difficult task. Interestingly, most psychotropic medications are not substrates for P-gp, and therefore reach adequate CNS concentrations. This makes some intuitive sense, since psychotropics need to achieve adequate levels within the CNS to be effective, and having a transport system that prevents their absorption into the CNS would most likely eliminate any potential for a drug to work psychotropically. Clearly more study is needed to fully understand the role of P-gp. Genetic differences may exist and environmental factors may alter its function by inhibition or induction. Additionally, many other drugs may inhibit or induce P-gp, creating clinical challenges or potential opportunities. Our breadth of knowledge of these specifics of P-gp is currently in its infancy. We expect to read much more about this transport enzyme in the next few years. —SCA
2. Concurrent Inhibition and Induction Greenblatt DJ, von Moltke LL, Daily JP, et al: Extensive impairment of triazolam and alprazolam clearance by shortterm low-dose ritonavir: the clinical dilemma of concurrent inhibition and induction. J Clin Psychopharmacol 1999; 19:293–296 Greenblatt DJ, von Moltke LL, Harmatz JS, et al: Alprazolamritonavir interaction: implications for product labeling. Clin Pharmacol Ther 2000; 67:335–341
Piscitelli SC, Kress DR, Bertz RJ, et al: The effect of ritonavir on the pharmacokinetics of meperidine and normeperidine. Pharmacotherapy 2000; 20:549– 553 Ritonavir is a protease inhibitor, one of the drugs commonly found in Highly Active Antiretroviral Therapy (HAART) or the “cocktail” for the treatment of Human Immunodeficiency Virus (HIV) infections. Ritonavir is the most potent inhibitor of CYP450 enzymes of the protease inhibitors. It is, in fact, a “pan-inhibitor,” having the ability to potently and competitively inhibit many if not all of the known CYP450 enzymes. This potential to inhibit the metabolism of drugs dependent on CYP450 enzymes for metabolism has led to multiple warnings in ritonavir’s product labeling, supported by many case reports and in vitro and in vivo studies. To add to this complexity, ritonavir is also an inducer of CYP4503A4. Briefly, to review the processes of induction and inhibition: induction increases enzyme production, where an inducing drug actually “encourages” the production of more enzyme (protein synthesis), making more sites available for metabolism. Induction takes several days to weeks to reach steady state in the presence of an inducing agent, and it also takes several weeks to return to normal metabolic rates, or to a normal number of enzyme sites. Conversely, competitive inhibition is immediate and occurs only in the presence of the inhibiting agent (the drug with the lower Ki, or the higher affinity for the enzyme). Inhibition leads to a slowed metabolism of parent drugs dependent on that occupied enzyme, which may lead to toxicity (as in the case of pimozide or the triazolobenzodiazepines alprazolam, triazoPsychosomatics 42:3, May-June 2001
Drug-Drug Interaction lam, and midazolam), or ineffectiveness (as in the case of codeine, which must be metabolized at CYP4502D6 to its active morphine compound). Once an inhibiting agent is discontinued, the inhibition of that metabolic site is over quickly (depending on the inhibitors half-life) and the site is open for metabolism of other agents. Greenblatt’s group provides a thorough review of the issues of inhibition and induction by a single agent: ritonavir. The first citation above is an editorial, but it is actually a well-written, concise review of the literature concerning concomitant inhibition and induction. The authors report that ritonavir might cause toxicity of drugs dependent on the CYP450 system for metabolism in the first few days but that this competitive inhibition is eventually diminished as the drug’s ability to induce metabolism takes full effect. They state that “the net effect of ritonavir on CYP3A-mediated metabolism in vivo represents a balance of inhibition and induction which is not easily predicted” (p. 294). Alprazolam and triazolam, as mentioned above, are triazolobenodiazepines, which are dependent on CYP4503A4 for metabolism. Short-term (32 hours) in vivo study of healthy volunteers reveals that ritonavir indeed impairs metabolism of alprazolam, leading to prolongation of elimination half-life, increase in total area under the concentration curve (AUC), and reduction of clearance. Importantly, Greenblatt’s group also studied the pharmacodynamic effects of this metabolic inhibition and found that there was an increase in sedation, an increase in beta amplitude on EEG, and an impairment in performance on the Digit Symbol Substitution Test. These authors cite a 10-day study where the effects of inhibition by ritonavir were not evident, probably because ritonaPsychosomatics 42:3, May-June 2001
vir’s ability to induce the same enzyme it inhibits balanced the effects found in shorter studies. A complicating factor in determining or predicting the effects of a drug like ritonavir is that most protease inhibitors also may inhibit P-gp, adding to the drug-response variability. Piscitelli et al. performed a 10-day crossover study of ritonavir and its effects on meperidine and normeperidine in healthy volunteers. They found meperidine’s AUC to be significantly reduced, not increased (as predicted in initial product labeling, which was based on in vitro and short- term studies). They found increased concentrations of normeperidine, the neurotoxic metabolite of meperidine, which has a longer half-life and has been found to cause delirium. The reason for increased levels of normeperidine is because the induced enzyme that metabolizes meperidine is now over-metabolizing and producing more of the toxic metabolite normeperidine. They did not study pharmacodynamic effects, and they did not study pain patients with long-term use of meperidine, where a decrease in parent compound may lead to breakthrough pain or withdrawal. The “take-home” message from these three papers is that product labeling needs to reflect more clearly the time course of drug interaction effects. Potent inhibitors like ritonavir will cause immediate drug interactions that may be toxic, but longer-term use of a drug that both inhibits and induces like ritonavir may lead to loss of clinical efficacy of the co-administered drug, accumulation of toxic metabolites, or in a best-case scenario, no overall adverse effects. Caution is always warranted with drugs dependent on CYP450 metabolism with narrow therapeutic windows or with toxic metabolites. Clinical monitoring and drug level sampling would be prudent. —KLC
3. Sildenafil (Viagra)
Warrington JS, Shader RI, von Moltke LL, et al: In vitro biotransformation of sildenafil (Viagra): identification of human cytochromes and potential drug interactions. Drug Metab Dispos 2000; 28:392–397
Muirhead GJ, Wulff MB, Fielding A, et al: Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir. Br J Clin Pharmacol 2000; 50:99–107 Just a quick review of sildenafil’s metabolic sites and potential drug interactions. Warrington et al. studied sildenafil in vitro using human liver microsomes and in microsomes containing heterologously expressed human chromosomes, using the inhibitors omeprazole (CYP450-2C19), quinidine (2D6), sulfaphenazole (2C9), ketoconazole (3A4), and ritonavir (all CYP450 enzymes). The authors found that sildenafil metabolism was inhibited by ketoconazole and ritonavir. The metabolite of sildenafil, UK-103,320 was formed by 3A4, 2C9, 2C19 and 2D6, the latter two contributing just 2%. The primary metabolic site for sildenafil in vitro was 3A4 and, to a much lesser extent, 2C9. Muirhead et al. studied the effect of two protease inhibitors on sildenafil in healthy volunteers in two studies of 28 volunteers each. They found that both protease inhibitors increased the Cmax, AUC, tmax, and half-life of sildenafil and its metabolite. Ritonavir 271
Drug-Drug Interaction had a greater impact on the increases than saquinavir, and the authors conclude that this may be due to ritonavir inhibiting both 3A4 and 2C9. They noted no adverse or more pronounced effects from the interactions. They do recommend a lower starting dose of sildenafil (25 mg) in patients already taking saquinavir and not to exceed a max-
272
imum of 25 mg in a 48-hour period for patients on ritonavir. Of note, these were small studies, and these were not ill patients on multiple medications. — KLC Dr. Armstrong is Co-Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest
Grove, OR; Dr. Cozza is an HIV Psychiatrist with the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC. Address correspondence to Dr. Armstrong, Tuality Forest Grove Hospital, 1809 Maple Street, Forest Grove, OR 97116, or scott.armstrong@ tuality.org.
Psychosomatics 42:3, May-June 2001