7-hydroxymethotrexate and Arthritis--Rheumatoid

The clinical pharmacokinetics of methotrexate, particularly when the drug is used at low doses for nonmalignant disease, are complicated and require extensive study. Bioavailability of the drug may be influenced--at least in part--by food intake. Biliary excretion can compensate for decreased renal excretion of methotrexate to some degree. However, further studies of the renal excretion of methotrexate are needed.

Topics: Animals; Arthritis, Rheumatoid; Bile; Biological Availability; Brain; Breast Neoplasms; Cell Line; Half-Life; Humans; Intestinal Absorption; Kidney; Kinetics; Liver; Metabolic Clearance Rate; Methotrexate; Neoplasms; Psoriasis; Tritium

Drugs prescribed for rheumatoid arthritis are often associated with gastrointestinal toxicity, and proton pump inhibitors may be coadministered for gastroprotection. In this open-label study, the effect of lansoprazole 30 mg qd and naproxen 500 mg bid on the pharmacokinetic profile of methotrexate was investigated. Twenty-seven adult rheumatoid arthritis patients on stable oral methotrexate doses (7.5-15 mg/week) for a minimum of 3 months were enrolled. Methotrexate pharmacokinetics were assessed on days -1 (methotrexate alone) and 7 (methotrexate with lansoprazole and naproxen). Pharmacokinetics of methotrexate and 7-hydroxymethotrexate were not altered by coadministration of methotrexate with lansoprazole and naproxen; point estimates and 90% confidence intervals for the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries. Therefore, coadministration of naproxen and lansoprazole for 7 days does not affect the pharmacokinetic profile of low doses of methotrexate.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Administration, Oral; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Area Under Curve; Arthritis, Rheumatoid; Dizziness; Dose-Response Relationship, Drug; Female; Headache; Humans; Lansoprazole; Male; Metabolic Clearance Rate; Methotrexate; Middle Aged; Naproxen; Nausea; Omeprazole; Vomiting

Methotrexate and nonsteroidal antiinflammatory drugs are frequently coadministered in the treatment of rheumatoid arthritis (RA).. To evaluate the effect of lumiracoxib, a novel cyclooxygenase-2 selective inhibitor, on methotrexate pharmacokinetics and short-term safety in patients with RA.. This multicenter, randomized, double-blind, placebo-controlled crossover study enrolled 18 patients (mean age 49.1 y) with stable RA. Patients were randomized to receive methotrexate 7.5-15 mg orally once weekly plus either lumiracoxib 400 mg/day or placebo for 7 days. Patients then received the other treatment combination for an additional 7 days. Serial blood and urine were collected for 24 hours after the methotrexate dose on day 1 (methotrexate alone) and days 8 and 15 (combination treatment).. Plasma methotrexate pharmacokinetics (AUC(0-t), maximum concentration [C(max)], time to C(max)) and methotrexate protein binding were similar for methotrexate alone (108.0 ng.h/mL, 26.7 ng/mL, 1.5 h, and 57.1%, respectively), methotrexate/lumiracoxib (110.2 ng.h/mL, 27.5 ng/mL, 1.0 h, and 53.7%, respectively), and methotrexate/placebo (101.8 ng.h/mL, 22.6 ng/mL, 1.0 h, and 57.0%, respectively). Similarly, no clinically significant difference was found in the urinary excretion of methotrexate. Mean exposure to the 7-OH metabolite was lower when methotrexate was given with lumiracoxib compared with placebo, shown by a reduction in AUC and C(max), although similar amounts of the metabolite were recovered in urine following both lumiracoxib and placebo. Coadministration of methotrexate and lumiracoxib was well tolerated.. Lumiracoxib had no significant effect on the pharmacokinetics, protein binding, or urinary excretion of coadministered methotrexate in patients with RA.

Topics: Adolescent; Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Cross-Over Studies; Cyclooxygenase 2; Diclofenac; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Female; Humans; Isoenzymes; Male; Membrane Proteins; Methotrexate; Middle Aged; Organic Chemicals; Prostaglandin-Endoperoxide Synthases

Rofecoxib is a highly selective and potent inhibitor of cyclooxgenase-2 (COX-2). Methotrexate is a disease-modifying agent with a narrow therapeutic index frequently prescribed for the management of rheumatoid arthritis. The objective of this study was to investigate the influence of clinical doses of rofecoxib on the pharmacokinetics of methotrexate in patients with rheumatoid arthritis. This was a randomized, double-blind, placebo-controlled study in 25 rheumatoid arthritis patients on stable doses of methotrexate. Patients received oral methotrexate (7.5 to 20 mg) on days -1, 7, 14, and 21. Nineteen patients received rofecoxib 12.5, 25, and 50 mg once daily on days 1 to 7, 8 to 14, and 15 to 21, respectively. Six patients received placebo on days 1 to 21 only to maintain a double-blinded design for assessment of adverse experiences. Plasma and urine samples were analyzed for methotrexate and its major although inactive metabolite, 7-hydroxymethotrexate. The AUC(0-infinity) geometric mean ratios (GMR) and their 90% confidence intervals (90% CI) (rofecoxib + methotrexate/methotrexate alone) for day 7/day -1, day 14/day -1, and day 21/day -1, for rofecoxib 12.5, 25, and 50 mg, were 1.03 (0.93, 1.14), 1.02 (0.92, 1.12), and 1.06 (0.96, 1.17), respectively (p > 0.2 for all comparisons to day -1). All AUC(0-infinity), GMR and Cmax GMR 90% CIs fell within the predefined comparability limits of (0.80, 1.25). Similar results were observed for renal clearance of methotrexate and 7-hydroxymethotrexate at the highest dose of rofecoxib tested (50 mg). It was concluded that rofecoxib at doses of 12.5, 25, and 50 mg once daily has no effect on the plasma concentrations or renal clearance (tested at the highest dose of rofecoxib) of methotrexate in rheumatoid arthritis patients.

Topics: Adult; Aged; Analysis of Variance; Antirheumatic Agents; Area Under Curve; Arthritis, Rheumatoid; Confidence Intervals; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Female; Folic Acid Antagonists; Humans; Lactones; Male; Methotrexate; Middle Aged; Sulfones

To determine if the pharmacokinetics of methotrexate (MTX) is modified by the coadministration of etodolac.. MTX (10 mg) was administered intramuscularly in the absence and presence of steady state levels of etodolac in 19 patients with rheumatoid arthritis. MTX levels were assayed by fluorescence polarization immunoassay. Concentrations of 7-hydroxymethotrexate (7-OH-MTX) were assayed by a reverse phase high performance liquid chromatography method. The unbound fraction was determined by ultrafiltration.. When etodolac was coadministered with MTX, the highest observed concentration decreased and the mean residence time increased to become statistically significant. However, these differences are not of great clinical importance especially given that the area under the curve and clearances were unchanged. There were no significant differences in binding protein and 7-OH-MTX concentrations between MTX with and without etodolac administration.. The pharmacokinetics of MTX is slightly modified by coadministration of etodolac. Moreover, no clinical toxicity was observed.

Topics: Adult; Aged; Arthritis, Rheumatoid; Blood Proteins; Drug Interactions; Etodolac; Female; Humans; Male; Methotrexate; Middle Aged; Protein Binding

1. The pharmacokinetics of MTX and its 7-hydroxy metabolite (7-OHMTX) were investigated in nine patients with rheumatoid arthritis (RA). Each patient received 15 mg MTX i.v., i.m. and p.o. after an overnight fast in a randomized cross-over design. The plasma concentrations of MTX and 7-OHMTX were measured over 7 days and their urinary excretion over 24 h. 2. Plasma concentrations of MTX were described by a triexponential function after i.v. administration, a triexponential function with zero or first order absorption after oral administration, and a biexponential function with zero of first order absorption after i.m. injection. Plasma concentrations of 7-OHMTX were described by a biexponential function after all three routes of administration. The median terminal elimination half-lives of MTX and 7-OHMTX were 55 h and 116 h, respectively. The area under the plasma concentration-time curve (AUC (0,170 h)) of MTX did not differ between i.m. and oral administration indicating similar bioavailability after these routes of administration. The AUC (0,170 h) values of 7-OHMTX after i.v., oral and i.m. administration were similar. Over 80% of MTX was excreted in urine as intact drug and about 3% was excreted as 7-OHMTX during 24 h after drug administration. 3. Plasma concentrations of MTX and 7-OHMTX were measurable at the end of the dose interval in most of the patients and may help to identify non-responders or patients with increased risk of side-effects.

Topics: Administration, Oral; Aged; Arthritis, Rheumatoid; Female; Folic Acid Antagonists; Humans; Injections, Intramuscular; Male; Methotrexate; Middle Aged

Methotrexate (MTX), an antifolate, is the anchor drug for the treatment of rheumatoid arthritis (RA). It is inexpensive, effective, and generally safe. When clinical response is inadequate, biological therapies are commonly used in combination with MTX. However, biological agents have safety concerns (i.e. infections, malignancy) and the addition of a biologic agent is expensive, making strategies to improve MTX efficacy important. Inhibition of pathways of folate metabolism involving purine metabolism by MTX, have been traditionally emphasized as important in MTX efficacy. However, inhibition MTX catabolism may also be important. MTX is irreversibly hydroxylated to form 7-hydroxy methotrexate (7-OH-MTX) by aldehyde oxidase (EC 1.2.3.1) (AOX). Catabolism of MTX to 7-OH-MTX is the first metabolic process imposed on an oral dose of MTX and will alter subsequent interactions of MTX with other enzymes. 7-OH-MTX is less potent than MTX in the treatment of rat adjuvant arthritis. RA patients with a low capacity to catabolize MTX to 7-OH-MTX do better clinically than individuals who are rapid formers of 7-OH-MTX. Therefore, altering the catabolism of MTX may be an innovative way to improve MTX efficacy. Raloxifene is a FDA-approved therapy for postmenopausal osteoporosis and for the reduction of invasive breast cancers but has no known activity in RA. Raloxifene is a potent inhibitor of human liver AOX. Postmenopausal women with RA frequently have low bone mineral density and would be candidates for raloxifene and MTX combination therapy. The effect of raloxifene on MTX metabolism has never been studied. Our hypothesis is that in postmenopausal women with RA and osteoporosis treated with MTX and raloxifene, the inhibition of AOX with resultant decreased formation of 7-OH MTX; will increase MTX levels and improve MTX efficacy. This hypothesis could be studied in an open-label, proof of concept clinical study in individuals before and after the addition of raloxifene. Red blood cell MTX and 7-OH-MTX levels and RA disease activity (DAS28) would be measured. In possible future studies, there are dietary substances, as supplements, (e.g. epigallocatechin gallate in green tea and resveratrol) which inhibit human liver AOX which could be evaluated.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Drug Therapy, Combination; Female; Folic Acid; Folic Acid Antagonists; Humans; Leucovorin; Male; Methotrexate; Osteoporosis; Purines; Raloxifene Hydrochloride; Rats; Rats, Inbred Lew; Treatment Outcome

Rheumatoid arthritis (RA) is a common autoimmune disease that causes significant disability and reduced life expectancy. The folate antagonist methotrexate (MTX) is first-line therapy for RA when used weekly at low doses (5-25 mg). However, the true rate of adherence to MTX is uncertain. This is in part due to the different methods of measurement of adherence employed with no biochemical test currently available to determine adherence to low dose MTX. Common methods of MTX measurement include immunoassays in patients with high dose therapy, but these assays cross-react with MTX metabolites and lack the sensitivity required to measure adherence to low dose MTX. HPLC-SRM-MS (selected reaction monitoring-mass spectrometry) has several theoretical advantages over immunoassays with improved specificity, minimal cross-reaction and higher sensitivity. The aim of this study was to develop an assay to measure MTX and its major metabolite 7-OH-MTX in urine as a tool to monitor adherence to low dose MTX in clinic. As a proof of concept, urine samples from 4 participants with RA were measured after directly observed therapy. The assay showed improved sensitivity compared to that reported by immunoassays, with low carryover and high within-run precision. In participant samples, MTX was measurable in the urine for up to 105 hours after administration and 7-OH-MTX was detectable up to 98 hours after administration, suggesting that this assay is suitable for the measurement of adherence to therapy. The assay requires minimal sample preparation and can be adopted by other laboratories with minimal study set up.

Topics: Arthritis, Rheumatoid; Chromatography, High Pressure Liquid; Drug Monitoring; Folic Acid Antagonists; Humans; Limit of Detection; Mass Spectrometry; Methotrexate

To assess the catabolism of methotrexate (MTX) to 7-hydroxy-MTX (7-OH-MTX) in patients with rheumatoid arthritis as well as the effect of folic acid and folinic acid on this catabolism.. Urinary excretion of MTX and its catabolite, 7-OH-MTX, was measured in 2 24-hour urine specimens collected after MTX therapy. Urine samples were collected from patients after the sixth and seventh weekly doses of MTX. MTX and 7-OH-MTX concentrations were determined by high-performance liquid chromatography mass spectrometry. Swelling and pain/tenderness indices were used to measure symptoms before and at 6 and 7 weeks of therapy. Patients received either folic acid or folinic acid supplements (1 mg/day) from week 6 to week 7.. Folic acid inhibited aldehyde oxidase (AO), the enzyme that produces 7-OH-MTX, but folinic acid did not. Excretion of 7-OH-MTX (determined as a percentage of the dose of MTX or as mg 7-OH-MTX/gm creatinine) was not normally distributed (n=39). Patients with marked improvement in swelling and pain/tenderness indices had a lower mean 7-OH-MTX excretion level (P<0.05). Patients who received folic acid supplements had decreased 7-OH-MTX excretion (P=0.03). Relatively high 7-OH-MTX excretion was correlated with relatively high MTX excretion and with relatively low MTX retention in vivo (P<0.05) (n=35).. Our findings of a non-normal distribution of 7-OH-MTX excretion suggest that there are at least 2 phenotypes for this catabolism. Decreased 7-OH-MTX formation suggests folic acid inhibition of AO and a better clinical response, while increased 7-OH-MTX formation may interfere with MTX polyglutamylation and binding to enzymes and, therefore, may increase MTX excretion and decrease MTX retention and efficacy in vivo.

Topics: Aldehyde Oxidase; Arthritis, Rheumatoid; Chromatography, High Pressure Liquid; Folic Acid; Health Status; Humans; Joints; Leucovorin; Methotrexate; Pain; Tandem Mass Spectrometry; Treatment Outcome

Topics: Arthritis, Rheumatoid; Humans; Methotrexate; Phenotype; Time Factors

To study the pharmacokinetics of methotrexate (MTX) plus cyclosporin A (CSA) in patients with rheumatoid arthritis (RA).. On day 1 of the study, patients with RA receiving stable doses of MTX had blood and urine levels of MTX and its metabolite 7-hydroxymethotrexate (7-OH-MTX) measured post oral dosing of the drug. MTX was then discontinued and CSA therapy was started on day 8. On day 20, blood levels of CSA and CSA metabolites were measured post drug dosing. On day 23, MTX therapy was restarted and levels of MTX, CSA and their metabolites were again measured as described above.. In the 30 patients, coadministration of CSA and MTX led to a 26% increase in mean peak plasma MTX concentration (P < 0.01), an 18% increase in the mean plasma MTX concentration area under the curve (AUC, P=0.01) and an 80% decrease in plasma 7-OH-MTX AUC (P < 0.01). In 13 patients receiving a 10 mg MTX dose, CSA reduced urinary 7-OH-MTX excretion by 87% (P < 0.01) without altering MTX excretion. MTX did not alter the pharmacokinetics of CSA or its metabolites.. CSA may block oxidation of MTX to its relatively inactive metabolite, 7-OH-MTX, thereby potentiating MTX efficacy.

Topics: Administration, Oral; Adult; Aged; Arthritis, Rheumatoid; Cyclosporine; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged

The pharmacokinetics of low dose methotrexate (MTX) were evaluated in 12 rheumatoid arthritis patients in the presence and absence of steady-state levels of salicylic acid (ASA) and sulindac (SU). Using a Latin square design, patients were given MTX plus ASA (mean 3.4 g/day), MTX plus SU (mean 400 mg/day), or MTX alone. On a background of at least one year of regular MTX therapy, patients received 10 mg/m2 MTX iv (mean 17.8 mg) given after at least 2 weeks of treatment with each of the above regimens. Plasma concentrations of MTX and 7-hydroxymethotrexate (7-OH-MTX) were measured using HPLC. No differences in MTX clearance (Cl) were found comparing MTX alone, MTX + ASA, and MTX + SU. However, if one particular subject that had a very low clearance when receiving MTX alone was excluded, there was a statistically significant decrease in MTX clearance when either ASA or SUL were present. It is also noteworthy that ASA significantly increased the exposure of the subject to 7-OH-MTX and, to a lesser extent, so did sulindac. Since 7-OH-MTX has been shown to be an active metabolite when given for cytotoxic effects at higher doses and because it has been show to be nephrotoxic at doses a thousand-fold greater than used in rheumatoid arthritis, nonsteroidal anti-inflammatory drugs should be used cautiously with MTX until further large scale safety studies are conducted. The data indicate that if a clinically significant interaction were to occur, ASA is more likely than SU to interact with MTX.

Topics: Arthritis, Rheumatoid; Aspirin; Drug Interactions; Female; Humans; Male; Methotrexate; Sulindac

We studied the pharmacokinetics of methotrexate (MTX) in a 64-year-old man with rheumatoid arthritis. After 6 months of treatment, acute clinical complications arose, requiring emergency laparotomy and cholecystotomy. A biliary tube was inserted, and this allowed for direct analysis of the bile. The pharmacokinetics of 2 separate doses of MTX (orally and intravenously) were assessed (dosage 10 mg/m2). No substantive differences in the pharmacokinetics were found between pre- and post-cholecystotomy MTX treatment, including clearance rates, volumes of distribution, and terminal half-lives. The results, however, demonstrated a change in the bioavailability of the drug (decreasing from 84.7% to 38.9%). Based on extrapolations of the data, with assumed rates of bile flow, the findings also suggest that there is substantial biliary elimination of MTX (8.7-26.0%) and its principal 7-hydroxy metabolite (1.5-4.6%).

Topics: Arthritis, Rheumatoid; Bile; Biological Availability; Drug Administration Schedule; Humans; Male; Methotrexate; Middle Aged; Osmolar Concentration