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• W2067814139 abstract "Drug interactions are an important avoidable cause of illness. With an increasing array of medications available to treat human disease and an increasing number of patients taking many medications, the risk of clinically significant drug interactions increases. This review describes some examples of common drug interactions in gastroenterology. The underlying mechanisms are discussed, and strategies are proposed to avoid drug interactions in clinical practice. Drug interactions are an important avoidable cause of illness. With an increasing array of medications available to treat human disease and an increasing number of patients taking many medications, the risk of clinically significant drug interactions increases. This review describes some examples of common drug interactions in gastroenterology. The underlying mechanisms are discussed, and strategies are proposed to avoid drug interactions in clinical practice. Every year, the arsenal of medications available to treat human disease becomes greater. This is certainly the case in gastrointestinal and liver diseases, in which exciting novel therapeutics are improving the lives of patients with inflammatory bowel disease, gastrointestinal motility disorders, and hepatitis C to name but a few examples. Optimum management of many diseases treated by gastroenterologists requires the use of more than one drug, and with advancing age, many of our patients have additional diseases that require drug therapy. Recent U.S. data indicate that almost 90% of individuals older than 65 years take regular prescription medications, and that people aged 50–64 years fill an average of 13 prescriptions per year, whereas those older than 80 years fill an average of 22 prescriptions in 1 year.1Agency for Healthcare Research and Quality and the National Center for Health StatisticsMedical Expenditure Panel survey. 1998Google Scholar In Sweden, a study of more than 5000 elderly outpatients showed that the average number of prescription medications taken by individuals in this demographic group was more than 5.2Bergendal L. Friberg A. Schaffrath A. Potential drug-drug interactions in 5,125 mostly elderly out-patients in Gothenburg, Sweden.Pharm World Sci. 1995; 17: 152-157Crossref PubMed Scopus (72) Google ScholarWith individual patients taking such large numbers of drugs comes the increased likelihood of unanticipated and unwanted clinical responses to drug combinations that differ from the known effects of the drugs when given alone. This review article provides examples of such drug interactions that occur commonly in gastroenterologic practice. The consequences of these interactions are shown, and the biological mechanisms that cause the unwanted effects are also explained. Most significant drug interactions are caused by a relatively small number of mechanisms, often by affecting the absorption, distribution, metabolism, or excretion of the drug. Knowledge of the underlying mechanism can be used to predict and prevent similar interactions between other drugs. Individuals who have inherited drug metabolizing enzymes of low activity as a result of genetic polymorphisms of the genes encoding those enzymes might be predisposed to interactions when they take drugs that are inactivated by that enzyme. Finally, general strategies are proposed to avoid the occurrence of clinically significant drug interactions.Case 1: reduced intestinal absorptionA 31-year-old man with advanced human immunodeficiency virus infection complicated by disseminated histoplasmosis was receiving maintenance itraconazole. He developed symptoms of gastroesophageal reflux. Omeprazole, a proton pump inhibitor, was prescribed. After 7 days of omeprazole therapy, the patient experienced a recrudescence of previously controlled histoplasmosis. Blood itraconazole levels were found to be subtherapeutic.What happened? Omeprazole therapy dramatically reduced gastric acid production and controlled symptoms of heartburn. However, absorption of itraconazole, which depends on an acidic environment in the upper gastrointestinal tract, was significantly reduced in the presence of impaired gastric acid production, resulting in subtherapeutic blood levels (Figure 1).3Jaruratanasirikul S. Sriwiriyajan S. Effect of omeprazole on the pharmacokinetics of itraconazole.Eur J Clin Pharmacol. 1998; 54: 159-161Crossref PubMed Scopus (107) Google ScholarCase 2: reduced renal excretionA 60-year-old woman was in a stable remission of Crohn’s disease on treatment with weekly subcutaneous methotrexate injections. She developed arthralgias that did not improve with acetaminophen, so she self-medicated with over-the-counter ibuprofen, which she took on a daily basis. After 4 weeks, she became fatigued and developed a fever and cough. Work-up showed pneumonia caused by Pneumocystis carinii infection. Hematologic analysis showed a leukocyte count of 0.9 × 109 per liter. Injections of fully reduced tetrahydrofolate (leucovorin) resulted in a prompt recovery of the leukocyte count to normal.What happened? Methotrexate is mostly eliminated by active renal tubular secretion into the urine. Ibuprofen decreases the excretion of weak acids, resulting in the retention of methotrexate and bone marrow suppression that can be reversed by administration of leucovorin (Figure 2). 4Tracy T.S. Krohn K. Jones D.R. Bradley J.D. Hall S.D. Brater D.C. The effects of a salicylate, ibuprofen, and naproxen on the disposition of methotrexate in patients with rheumatoid arthritis.Eur J Clin Pharmacol. 1992; 42: 121-125Crossref PubMed Scopus (108) Google ScholarFigure 2The methotrexate-ibuprofen interaction is caused by a pharmacokinetic mechanism at the level of methotrexate excretion.View Large Image Figure ViewerDownload (PPT)Case 3: Reduced first-pass metabolismA 44-year-old woman was doing well 2 years after orthotopic liver transplantation on cyclosporine-based immunosuppression. She became concerned about low vitamin C intake, so she began to consume a large glass of grapefruit juice every morning. After 7 days she developed headaches and became tremulous. Her blood pressure measurements and serum creatinine level were found to be elevated. Blood cyclosporine concentration was 450 ng/mL, well above the therapeutic range. Temporary cessation of cyclosporine until the blood concentration normalized resulted in clinical resolution.What happened? A constituent of grapefruit juice decreases the expression of intestinal cytochrome P450 isoform 3A4 activity, a major pathway of cyclosporine inactivation.5Hollander A.A. van Rooij J. Lentjes G.W. Arbouw F. van Bree J.B. Schoemaker R.C. van Es L.A. van der Woude F.J. Cohen A.F. The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients.Clin Pharmacol Ther. 1995; 57: 318-324Crossref PubMed Scopus (107) Google Scholar This leads to dramatically reduced first-pass metabolism of cyclosporine and results in elevation of blood cyclosporine concentration and consequent symptoms of toxicity (Figure 3). A similar decrease in cyclosporine inactivation occurs when it is co-administered with another cytochrome P450 3A4 inhibitor, ketoconazole. In fact, the concomitant administration of ketoconazole has been proposed as a way to decrease the dose of cyclosporine needed to prevent transplanted organ rejection.6Keogh A. Spratt P. McCosker C. Macdonald P. Mundy J. Kaan A. Ketoconazole to reduce the need for cyclosporine after cardiac transplantation.N Engl J Med. 1995; 333: 628-634Crossref PubMed Scopus (132) Google ScholarFigure 3The cyclosporine-grapefruit juice interaction is caused by a pharmacokinetic mechanism at the level of cyclosporine first-pass metabolism.View Large Image Figure ViewerDownload (PPT)Case 4: Reduced inactivationA 71-year-old man was in a stable condition taking azathioprine for Crohn’s disease, when he developed acute gout. After the acute attack subsided, the xanthine oxidase inhibitor, allopurinol, was prescribed to prevent recurrences of gout. Two weeks later, the patient visited his physician because of fatigue, and a blood count showed a leukocyte count of 1.1 × 109 per liter, along with marked anemia and thrombocytopenia. Temporary cessation of azathioprine was followed by normalization of hematologic parameters.What happened?Allopurinol inhibits xanthine oxidase, the rate-limiting enzyme of one of the chief metabolic pathways available for azathioprine metabolism.7Prager D. Rosman M. Bertino J.R. Letter: azathioprine and allopurinol.Ann Intern Med. 1974; 80: 427Crossref PubMed Scopus (7) Google Scholar, 8Brooks R.J. Dorr R.T. Durie B.G. Interaction of allopurinol with 6-mercaptopurine and azathioprine.Biomed Pharmacother. 1982; 36: 217-222PubMed Google Scholar As a result, a greater proportion of the drug undergoes conversion to 6-thioguanine, the active metabolite of azathioprine. This results in excessive bone marrow suppression by 6-thioguanine nucleotides (Figure 4).Figure 4The azathioprine-allopurinol interaction is caused by a pharmacokinetic mechanism at the level of azathioprine metabolism.View Large Image Figure ViewerDownload (PPT)Case 5. Increased hepatic inactivationA 46-year-old woman with a history of spontaneous acute mesenteric vein thrombosis was found to have the Factor V Leiden mutation, and lifelong warfarin was recommended. She took a steady dose of warfarin. Later, she experienced an acute epileptic seizure, and phenobarbital was administered. Two weeks later, she developed acute abdominal pain and was found to have a recurrence of acute mesenteric vein thrombosis. Her international normalized ratio was 1.0.What happened? Phenobarbital induces the expression of certain hepatic cytochromes P450, resulting in increased inactivation of drugs that are metabolized by these enzymes, such as warfarin.9MacDonald M.G. Robinson D.S. Clinical observations of possible barbiturate interference with anticoagulation.JAMA. 1968; 204: 97-100Crossref PubMed Scopus (46) Google Scholar Consequently, the anticoagulant activity of warfarin was diminished, predisposing this patient to recurrent spontaneous thrombosis (Figure 5).Figure 5The warfarin-phenobarbital interaction is caused by a pharmacokinetic mechanism at the level of warfarin inactivation.View Large Image Figure ViewerDownload (PPT)Case 6: Synergistic effectsA 61-year-old woman was taking warfarin for chronic atrial fibrillation. She developed joint pain and self-medicated with aspirin. Seven days later she had melena and was found to have several small gastric erosions that were oozing blood. Hematologic evaluation was normal apart from an international normalized ratio of 2.0.What happened? Both warfarin and aspirin decrease the ability of the blood to clot, but by different mechanisms. Warfarin inhibits production of vitamin K-dependent factors in the clotting cascade, whereas aspirin inhibits platelet function. Therefore, in combination, their anticoagulant effects are synergistic and in this case resulted in excessive loss of normal hemostatic mechanisms.10Sebastian J.L. Tresch D.D. Use of oral anticoagulants in older patients.Drugs Aging. 2000; 16: 409-435Crossref PubMed Scopus (35) Google Scholar Aspirin can also injure the gastric mucosa, which likely contributed to the bleeding in this case (Figure 6). Both warfarin and aspirin are heavily plasma protein bound, so the addition of aspirin to regular warfarin therapy might displace warfarin from plasma protein binding, resulting in a temporary increase in free plasma warfarin. However, the warfarin displaced from binding to plasma proteins by aspirin is rapidly distributed and metabolized, so equilibrium is reestablished with very similar amounts of free drug in plasma. The lack of elevation of international normalized ratio above therapeutic levels in this case shows that this pharmacokinetic mechanism was not an important contributor to this interaction.11Fiske W.D. Connell J.M. Benedek I.H. Lack of pharmacokinetic interaction between aspirin and warfarin.Am J Ther. 1995; 2: 407-413PubMed Google ScholarFigure 6The warfarin-aspirin interaction is caused by a combination of pharmacodynamic mechanisms that result in greater anticoagulant effects.View Large Image Figure ViewerDownload (PPT)Case 7: Antagonistic effectsA 55-year-old man with cirrhosis of the liver and portal hypertension had ascites that was well-controlled on a low-sodium diet and stable doses of spironolactone and furosemide. He developed painful osteoarthritis of the knees and self-medicated with over-the-counter indomethacin. After a few days, he noticed a gradual recurrence of leg edema, abdominal fullness, and weight gain. Examination confirmed the presence of ascites.What happened? The cirrhotic state causes intense sodium retention by the kidneys, which in many patients must be counterbalanced by diuretic therapy to promote sodium excretion. Nonsteroidal anti-inflammatory drugs such as indomethacin inhibit the production of prostaglandins in the kidney, which are essential for maintenance of adequate glomerular filtration rates. In this case, the natriuretic effects of diuretics were negated by reduced renal blood flow caused by lowering of prostaglandin levels by indomethacin, resulting in sodium and water retention (Figure 7).Figure 7The furosemide-indomethacin interaction is caused by a pharmacodynamic mechanism at the level of renal sodium handling.View Large Image Figure ViewerDownload (PPT)Case 8: Idiosyncratic interactionA 71-year-old man with Parkinson’s disease was being treated with selegiline, a monoamine oxidase inhibitor. He presented for colonoscopy and received conscious sedation, which included meperidine. During the procedure, the patient’s blood pressure increased dramatically; he became febrile and had a tonic-clonic seizure.What happened? This is an example of an idiosyncratic drug reaction in which 2 co-administered drugs cause a severe effect that is not typical for either drug alone (Figure 8). This interaction can occur when other monoamine oxidase inhibitors are co-administered with several opiates.12Zornberg G.L. Bodkin J.A. Cohen B.M. Severe adverse interaction between pethidine and selegiline.Lancet. 1991; 337: 246Abstract PubMed Scopus (79) Google ScholarFigure 8The cause of the selegiline-meperidine interaction is obscure.View Large Image Figure ViewerDownload (PPT)Drug interactions: Basic mechanismsAs illustrated in these examples, one drug or a foodstuff can interact with another drug by affecting its absorption, distribution, metabolism, or excretion, so-called pharmacokinetic interactions. In these types of interactions, the concentration of drug at the effect site is altered, producing either excessive or inadequate effects that generally can be predicted on the basis of the known effects of the drug. For these types of interactions to be clinically significant, the drug whose effect is altered must have a narrow therapeutic window, i.e., the concentration range within which the drug is effective but not toxic must be small. Many drugs have very wide therapeutic windows and thus are intrinsically unlikely to be involved in clinically significant drug interactions based on pharmacokinetics. Another prerequisite for drug interactions of the pharmacokinetic type to reach clinical significance is the presence of a steep dose-response curve for the affected drug, that is, there is a large difference in effect with a relatively small difference in drug concentration. If sharp changes in drug concentration induced by an interacting drug do not significantly affect the responses caused by that drug, then the interaction is unlikely to be noticed.Of particular importance in pharmacokinetic drug interactions are the inducers and inhibitors of hepatic microsomal cytochromes P450. These are the heme-containing enzymes responsible for inactivation of the majority of xenobiotic substances (exogenous chemicals), including drugs that we encounter in our lives. The expression levels of various cytochromes P450 are increased by certain drugs, leading to the presence of greater enzymatic activity and consequently faster rates of inactivation of the drug substrates for the induced enzyme (Table 1). This can lead to lower drug concentrations and loss of effect. Conversely, certain drugs tend to inhibit the activity of cytochromes P450 and consequently increase the concentration of drugs that are also inactivated by the inhibited cytochrome P450 (Table 2). In many drug interactions that are due to a reduction in the rate of inactivation, the interacting drugs are both substrates for the same cytochrome P450. In this situation, the drug with the lower affinity for the enzyme will be metabolized more slowly than the drug with high affinity, leading to an elevation in the concentration of that drug. Many drugs can be metabolized by more than one member of the cytochrome P450 family, so reduced access to the usual route of inactivation might be partly compensated by the action of another enzyme with a lower affinity for that drug, thus reducing the impact of the interaction. The low substrate specificity of cytochromes P450 and the resulting redundancy in pathways of xenobiotic detoxification might represent an evolutionary mechanism of resistance to the potentially harmful effects of environmental toxins that we encounter, including drugs.Table 1Some Important Inducers of Cytochromes P450 and Commonly Affected DrugsCommon P450 inducers (P450 affected)Ethanol (2E1)Carbamazepine (3A4, 5, 7)Phenobarbital (2B6, 3A4, 5, 7)Phenytoin (3A4, 5, 7)Rifampicin (2C9)Commonly affected drugs (P450 involved)Warfarin (2C9)Corticosteroids (2C19)Cyclosporine (3A4)Birth control pills (3A4) Open table in a new tab Table 2Some Important Inhibitors of Cytochromes P450Cytochrome P450InhibitorAffected drug3A4ErythromycinCyclosporine3A4RitonavirSaquinavir3A4CimetidineAmiodarone, phenytoin1A2CiprofloxacinTheophylline2C9IsoniazidWarfarin Open table in a new tab It has been recognized for decades that an individual’s capacity to metabolize certain drugs is an inherited trait.13Weinshilboum R. Inheritance and drug response.N Engl J Med. 2003; 348: 529-537Crossref PubMed Scopus (911) Google Scholar Thus, in a population, one can identify groups of people who have low, intermediate, or high capacity to metabolize a drug or a class of drugs. In the genomic era, it has become clear that this variation is due to polymorphisms (common natural variations) in the sequences of genes encoding the enzymes that metabolize drugs. Generally, if an individual inherits 2 normal copies of the gene, they have high activity of the encoded enzyme; with 1 normal and 1 abnormal copy, they have intermediate activity; and with 2 abnormal copies they have low or absent activity. Individuals who inherit low activity of a drug metabolizing enzyme are at increased susceptibility for clinically significant drug interactions when they take a drug that is metabolized by that enzyme. Currently, testing for polymorphisms of drug metabolizing enzymes is clinically available only for a very small number of enzymes, such as thiopurine methyltransferase.13Weinshilboum R. Inheritance and drug response.N Engl J Med. 2003; 348: 529-537Crossref PubMed Scopus (911) Google Scholar However, in the near future, the ability to individualize drug therapy on the basis of genetic polymorphisms might be one of the first clinical payoffs of genomics, so-called pharmacogenomics.Pharmacodynamic drug interactions are those in which the effect of a drug is modified by another drug that does not affect the concentration of the other. Interactions of this type primarily occur when drugs with synergistic or antagonistic affects are co-administered. Clinically significant idiosyncratic drug interactions are fortunately quite rare, because the drugs that are susceptible to such interactions are recognized as being less safe than alternative counterparts for given indications.Drug interactions: How to avoidThe busy practicing physician must develop strategies that promote safe prescribing habits. One element of safe prescribing is to be alert to potential interactions between medications that the patient is already taking and the new drug being considered. First and foremost, polypharmacy must be avoided whenever possible. The potential for clinically significant drug interactions increases with the number of medications being taken, so a careful periodic review of the list of medications being taken by the patient is important, and every opportunity should be taken to discontinue unnecessary medications.2Bergendal L. Friberg A. Schaffrath A. Potential drug-drug interactions in 5,125 mostly elderly out-patients in Gothenburg, Sweden.Pharm World Sci. 1995; 17: 152-157Crossref PubMed Scopus (72) Google Scholar, 14Herrlinger C. Klotz U. Drug metabolism and drug interactions in the elderly.Best Pract Res Clin Gastroenterol. 2001; 15: 897-918Abstract Full Text PDF PubMed Scopus (90) Google Scholar Special care must also be taken to ascertain whether the patient takes any over-the-counter or “alternative” medications. Pharmacists routinely evaluate potential drug interactions, but they might not be aware of all drugs taken by the patient. Individual patients at high risk for drug interactions should be recognized. Groups who have been identified as being at high risk for drug interactions include the elderly, the critically ill, and human immunodeficiency virus-infected patients.15McLennon S.M. Smith R. Orrick J.J. Recognizing and preventing drug interactions in older adults with HIV.J Gerontol Nurs. 2003; 29: 5-12PubMed Google Scholar Extra caution should be exercised in these patient groups when prescribing new medications. The safety profiles of the drugs taken by the patient should be known. As discussed above, many drugs are relatively unlikely to be involved in clinically significant drug interactions, whereas others with more narrow therapeutic windows or more serious potential adverse effects must be more closely evaluated. Drugs that induce or inhibit the cytochrome P450 system are particularly important, because they can affect the metabolism of many other drugs.ConclusionIn summary, understanding the principles and mechanisms of drug interactions will allow the prescriber to recognize situations in which clinically significant interactions are most likely to occur. A number of useful electronic resources are available to physicians and patients to check on potential drug interactions (Table 3). If in doubt, consultation with a pharmacist will allow the prescriber to obtain the latest information on a potential interaction and to evaluate alternative therapies that might be more suitable.Table 3Strategies to Avoid Significant Drug InteractionsStrategyIdentify high risk patientsElderlyCritically illHIV infectionIdentify high risk drugsDrug metabolizing enzyme inducers and inhibitorsDrugs with narrow therapeutic windowDrugs with serious adverse effectsDrugs with known idiosyncratic interactionsCheck current medicationsAvoid unnecessary polypharmacyConsultationPharmacistElectronic database, e.g., Micromedex, ePocratesWebsites, e.g., http://www.drugdigest.org/DD/Interaction/ChooseDrugs, http://medicine.iupui.edu/flockhart/HIV, human immunodeficiency virus. Open table in a new tab Every year, the arsenal of medications available to treat human disease becomes greater. This is certainly the case in gastrointestinal and liver diseases, in which exciting novel therapeutics are improving the lives of patients with inflammatory bowel disease, gastrointestinal motility disorders, and hepatitis C to name but a few examples. Optimum management of many diseases treated by gastroenterologists requires the use of more than one drug, and with advancing age, many of our patients have additional diseases that require drug therapy. Recent U.S. data indicate that almost 90% of individuals older than 65 years take regular prescription medications, and that people aged 50–64 years fill an average of 13 prescriptions per year, whereas those older than 80 years fill an average of 22 prescriptions in 1 year.1Agency for Healthcare Research and Quality and the National Center for Health StatisticsMedical Expenditure Panel survey. 1998Google Scholar In Sweden, a study of more than 5000 elderly outpatients showed that the average number of prescription medications taken by individuals in this demographic group was more than 5.2Bergendal L. Friberg A. Schaffrath A. Potential drug-drug interactions in 5,125 mostly elderly out-patients in Gothenburg, Sweden.Pharm World Sci. 1995; 17: 152-157Crossref PubMed Scopus (72) Google Scholar With individual patients taking such large numbers of drugs comes the increased likelihood of unanticipated and unwanted clinical responses to drug combinations that differ from the known effects of the drugs when given alone. This review article provides examples of such drug interactions that occur commonly in gastroenterologic practice. The consequences of these interactions are shown, and the biological mechanisms that cause the unwanted effects are also explained. Most significant drug interactions are caused by a relatively small number of mechanisms, often by affecting the absorption, distribution, metabolism, or excretion of the drug. Knowledge of the underlying mechanism can be used to predict and prevent similar interactions between other drugs. Individuals who have inherited drug metabolizing enzymes of low activity as a result of genetic polymorphisms of the genes encoding those enzymes might be predisposed to interactions when they take drugs that are inactivated by that enzyme. Finally, general strategies are proposed to avoid the occurrence of clinically significant drug interactions. Case 1: reduced intestinal absorptionA 31-year-old man with advanced human immunodeficiency virus infection complicated by disseminated histoplasmosis was receiving maintenance itraconazole. He developed symptoms of gastroesophageal reflux. Omeprazole, a proton pump inhibitor, was prescribed. After 7 days of omeprazole therapy, the patient experienced a recrudescence of previously controlled histoplasmosis. Blood itraconazole levels were found to be subtherapeutic.What happened? Omeprazole therapy dramatically reduced gastric acid production and controlled symptoms of heartburn. However, absorption of itraconazole, which depends on an acidic environment in the upper gastrointestinal tract, was significantly reduced in the presence of impaired gastric acid production, resulting in subtherapeutic blood levels (Figure 1).3Jaruratanasirikul S. Sriwiriyajan S. Effect of omeprazole on the pharmacokinetics of itraconazole.Eur J Clin Pharmacol. 1998; 54: 159-161Crossref PubMed Scopus (107) Google Scholar A 31-year-old man with advanced human immunodeficiency virus infection complicated by disseminated histoplasmosis was receiving maintenance itraconazole. He developed symptoms of gastroesophageal reflux. Omeprazole, a proton pump inhibitor, was prescribed. After 7 days of omeprazole therapy, the patient experienced a recrudescence of previously controlled histoplasmosis. Blood itraconazole levels were found to be subtherapeutic. What happened? Omeprazole therapy dramatically reduced gastric acid production and controlled symptoms of heartburn. However, absorption of itraconazole, which depends on an acidic environment in the upper gastrointestinal tract, was significantly reduced in the presence of impaired gastric acid production, resulting in subtherapeutic blood levels (Figure 1).3Jaruratanasirikul S. Sriwiriyajan S. Effect of omeprazole on the pharmacokinetics of itraconazole.Eur J Clin Pharmacol. 1998; 54: 159-161Crossref PubMed Scopus (107) Google Scholar Case 2: reduced renal excretionA 60-year-old woman was in a stable remission of Crohn’s disease on treatment with weekly subcutaneous methotrexate injections. She developed arthralgias that did not improve with acetaminophen, so she self-medicated with over-the-counter ibuprofen, which she took on a daily basis. After 4 weeks, she became fatigued and developed a fever and cough. Work-up showed pneumonia caused by Pneumocystis carinii infection. Hematologic analysis showed a leukocyte count of 0.9 × 109 per liter. Injections of fully reduced tetrahydrofolate (leucovorin) resulted in a prompt recovery of the leukocyte count to normal.What happened? Methotrexate is mostly eliminated by active renal tubular secretion into the urine. Ibuprofen decreases the excretion of weak acids, resulting in the retention of methotrexate and bone marrow suppression that can be reversed by administration of leucovorin (Figure 2). 4Tracy T.S. Krohn K. Jones D.R. Bradley J.D. Hall S.D. Brater D.C. The effects of a salicylate, ibuprofen, and naproxen on the disposition of methotrexate in patients with rheumatoid arthritis.Eur J Clin Pharmacol. 1992; 42: 121-125Crossref PubMed Scopus (108) Google Scholar A 60-year-old woman was in a stable remission of Crohn’s disease on treatment with weekly subcutaneous methotrexate injections. She developed arthralgias that did not improve with acetaminophen, so she self-me" @default.
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