Urinary Excretion Of Methotrexate Research Articles

AB0363 Coadministration of asp015k, a novel janus kinase inhibitor, with methotrexate demonstrates tolerability and lack of pharmacokinetic interactions in patients with rheumatoid arthritis

BackgroundASP015K is an oral Janus kinase (JAK) inhibitor with selectivity for JAK1/3 in development for treatment of rheumatoid arthritis (RA) and other autoimmune diseases. Methotrexate (MTX) is the most common...

Fostamatinib, a Syk-Kinase Inhibitor, Does Not Affect Methotrexate Pharmacokinetics in Patients With Rheumatoid Arthritis

Fostamatinib (R788) is being investigated as an add-on therapy for the treatment of rheumatoid arthritis (RA) in patients with inadequate response to methotrexate (MTX). This study evaluated the potential pharmacokinetic interaction between R788 and MTX. Sixteen RA subjects on a stable weekly MTX regimen were enrolled and received MTX on days 1 and 8. Twelve subjects received 100 mg of R788 orally, and 4 subjects received a matching placebo twice daily from days 4 to 8 and once daily on days 3 and 9. Blood samples were collected on days 1 and 8 for MTX and 7-hydroxymethotrexate (7-OH-MTX), and days 3 and 9 for R788 and its active metabolite, R406. MTX and 7-OH-MTX pharmacokinetic parameters were similar on days 1 and 8. In the R788 group, the mean day 8 to day 1 ratios (90% confidence intervals) of maximum concentration and area under the plasma concentration-time curve estimates were 1.01 (0.85-1.20) and 1.12 (0.90-1.40) for MTX and 1.06 (0.82-1.35) and 1.06 (0.83-1.36) for 7-OH-MTX, respectively. Urinary excretion of MTX and 7-OH-MTX was also similar with or without R788, averaging 58% to 69% and 4% to 5% of the MTX dose, respectively. The data suggest that there is no clinically significant pharmacokinetic interaction of R788 and MTX in RA patients.

Effect of Nonsteroidal Anti-inflammatory Drugs on Pharmacokinetics of Methotrexate: A Meta-analysis

It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) affect the pharmacokinetics of methotrexate, but there are several reports showing negative consequences. In this study, we evaluated drug interactions by performing a meta-analysis on published data examining the effect of NSAIDs on pharmacokinetic parameters of methotrexate. The combined standardized mean difference of the maximum blood concentration after oral administration of methotrexate was calculated to be -0.00 (95% confidence interval, -0.30 to 0.30) based on 6 clinical trials, and there was no significant effect of NSAIDs (p=0.9967). However, it is also represented that the NSAIDs significantly increased the area under the blood concentration-time curve of methotrexate (combined standardized mean difference, 0.73; 95% confidence interval, 0.32 to 1.14; p=0.0004; 11 trials). Furthermore, the combined standardized mean differences in total and renal clearance of methotrexate were estimated to be -0.80 (95% confidence interval, -1.41 to -0.18; p=0.0109; 6 trials) and -0.76 (95% confidence interval, -1.40 to -0.11; p=0.0220; 11 trials), respectively, implying that NSAIDs interfere with urinary excretion of methotrexate. In conclusion, the integration of the published reports by these meta-analyses shows that NSAIDs increase blood levels of methotrexate by influencing renal excretion of the antifolate.

Drug interaction between celecoxib and methotrexate in organic anion transporter 3–transfected renal cells and in rats in vivo

Methotrexate has a clinically important pharmacokinetic interaction with nonsteroidal anti-inflammatory drugs (NSAIDs) mainly through its competition for tubular secretion via the renal organic anion transporter 3 (OAT3). We have previously reported the usefulness of OAT3-transfected renal tubular cells for screening of the drugs which interfere with the pharmacokinetics of methotrexate. Celecoxib, a cyclooxygenase (COX) 2 inhibitor, has not been reported to interact with methotrexate, but the mechanisms are unclear why the interaction did not occur. The purpose of this study was to evaluate the effect of celecoxib on methotrexate tubular secretion using a renal cell line stably expressing human OAT3 (S2-hOAT3), and to evaluate the pharmacokinetic interaction of the two drugs in rats. [ 3H]methotrexate uptake into S2-hOAT3 cells was significantly inhibited by celecoxib in a concentration-dependent manner and the Ki value was 35.3 µM. However, methotrexate serum concentrations and urinary excretion of methotrexate over 24 h in rats were not affected by celecoxib (50, 200 mg/kg). Celecoxib serum concentrations were increased by the increase in celecoxib dosage and the maximum drug concentration (Cmax) was 20.6 µM (celecoxib 200 mg/kg), which did not reach the Ki value obtained in the in vitro study. These results indicated that celecoxib inhibited the secretion of methotrexate via hOAT3, which suggested that celecoxib was a substrate of hOAT3. However, co-administration of the two drugs at clinical dosage did not affect the pharmacokinetics of methotrexate, because the serum concentrations did not reach the Ki value. Although the accumulation study using S2-hOAT3 cells was useful to predict the interaction between the new drug and methotrexate in vivo, a comparison of the Ki value with the Cmax in clinical dosage was necessary to evaluate the degree of this interaction.

Methotrexate catabolism to 7-hydroxymethotrexate in rheumatoid arthritis alters drug efficacy and retention and is reduced by folic acid supplementation.

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.

Potential for methotrexate exposure through contamination during parenteral use as an immunosuppressant

To evaluate whether the risk of methotrexate (MTX) exposure through skin contamination using parenteral doses of 25 mg warrants special oncology handling precautions during administration. We conducted a study with six human volunteers deliberately exposed to an entire dose of 25 mg MTX solution on their skin for 30 min. Serum levels of MTX were measured at baseline, 2, 4, 8, 12 and 24 h as well as serum homocysteine at baseline and 24 h after clinical exposure. Twenty-four-hour urinary excretion of MTX and possible local or systemic signs of toxicity were also recorded. All MTX serum concentrations were less than 0.02 micromol/L within the 24-h period. This is 500 times below the recommended serum concentration for which folinic acid supplementation is recommended. There was also no significant increase in homocysteine level to suggest MTX toxicity. The only adverse effects were mild local dermal reactions in three female volunteers. Deliberate skin contamination and possible inhalation of a 25 mg MTX solution failed to show significant or quantifiable serum and urine concentrations to suggest MTX toxicity. Precautions to prevent contact with MTX designed for oncology protocols are unnecessary for our rheumatology patients or their carers using these much lower immunosuppressant doses for autoimmune diseases.

Role of kidney-specific organic anion transporters in the urinary excretion of methotrexate

High-dose folinic acid is used to accelerate methotrexate elimination to avoid renal toxicity of the drug. The present study was carried out to examine the role of the renal organic anion transporters OAT-K1 and OAT-K2 in the urinary excretion of methotrexate, especially in the methotrexate-folinic acid rescue therapy. Madin-Darby canine kidney cells stably expressing OAT-K1 and OAT-K2 were used for the in vitro transport study; 5/6 nephrectomized rats were used to detect changes in mRNA expression levels of OAT-K1 and OAT-K2 and to evaluate methotrexate pharmacokinetics under conditions of renal insufficiency. Methotrexate efflux mediated by these transporters in stable transfectants was stimulated in the presence of extracellular folic acid and folinic acid, suggesting that they could serve as anion exchangers to enhance the apical efflux of methotrexate. The mRNA expression levels of OAT-K1 and OAT-K2 were markedly diminished after 5/6 nephrectomy, but those of multidrug resistance associated protein 2, which could transport methotrexate, were maintained. Renal clearance of methotrexate was markedly decreased in 5/6 nephrectomized rats compared with that in sham-operated rats. Additional folinic acid treatment resulted in a significant increase in methotrexate renal clearance in sham-operated rats but not in 5/6 nephrectomized rats. The decreased expressions of OAT-K1 and OAT-K2 may be attributable to the longer exposure to methotrexate and ineffective folinic acid rescue. In terms of contributing to patient safety, renal clearance of methotrexate, especially folinic acid-stimulated tubular secretion of the drug via these transporters, would be a key factor in methotrexate therapy.

Nonlinear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption.

The plasma concentration and urinary excretion of methotrexate were followed in twelve psoriatic patients after intravenous and oral doses of methotrexate ranging from 7.5 to 30 mg. In six of the patients, a nonlinear relation was found between the fractional amount of methotrexate excreted in the urine and the corresponding area under the plasma concentration-time curve. The methotrexate clearance was found to be increased during the initial high plasma concentration, probably due to saturation of the tubular reabsorption of methotrexate. Considerable interindividual variation was found in the apparent saturation point of the active reabsorption, but up to 500-800 ng/ml first order kinetics still applied. At plasma concentrations below saturation, the renal clearance of methotrexate ranged from 52-102 ml/min (mean +/- SD, 83 +/- 19.4 ml/min).

HIGH DOSE METHOTREXATE TREATMENT OF CHILDREN WITH ALL

A clinical trial with HDM as consolidation therapy in ALL was started in June 1975. Three courses of HDM, 500 mg/sq.m. at 3-weekly intervals have been used in 74 children with ALL and one with AML. Fourty-six of 53 patients in primary complete remission have been in sustained remission for 6-39 months.The pharmacokinetics of HDM treatment were studied in 11 of these patients and in six other patients with far advanced lymphatic leukemia and other malignancies given a much higher dose of methotrexate (2790 ± 1010 mg/sq.m.). The decay of serum concentration of methotrexate was found to follow a diphasic curve, with an initial serum half-life of 4.8 hours followed by a second half life of 34.4 hours. Apparent volume of distribution was 56.8 litres/sq.m. and distribution equilibrium was not reach before approx. forty hours after start of infusion. Significant levels of methotrexate were found in the cerebrospinal fluid, but the penetration to the cerebrospinal fluid was slow. The concentrations are, however, comparable to those obtained in ventricular fluid after lumbar administration of from 6.25 - 12.5 mg methotrexate/sq.m. Urinary excretion of methotrexate was considerable, and might exceed the limit for methotrexate solubility if the urine is not alkalinized.

Pharmacokinetics of high-dose methotrexate treatment in children.

The pharmacokinetics of intravenous high-dose methotrexate were studied in two groups of children being treated for malignant diseases, mostly acute lymphatic leukemia. The peak serum level of methotrexate of 2.32--10(-5) mol/1 was found in children given 500 mg methotrexate/m2 by a 24 h infusion, and another group given 2790 mg/m2 during a 6 h infusion had serum levels as high as 2.16--10(-4) mol/1. The decay of serum concentration of methotrexate after completion of the infusion followed a diphasic curve, with an initial serum half-life of 4.8 h, followed by a second half-life of 34.4 h at distribution equilibrium. The apparent volume of distribution was 56.8 litres/m2. Significant levels of methotrexate were found in cerebrospinal fluid, but penetration into cerebrospinal fluid was slow. Urinary excretion of methotrexate was considerable. Four to five days after commencement of the infusion, urinary concentrations of methotrexate still exceeded the serum levels.