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PubMed1979

Comparison of intravenous and oral high-dose methotrexate in treatment of solid tumours.

An outpatient regimen of oral high-dose methotrexate was studied in 14 patients with solid tumours over 12 months. Detailed pharmacokinetic analysis in five patients showed high oral bioavailability (mean +/- SE of mean 87.6 +/- 1.5%), indicating that with this regimen oral methotrexate was well absorbed and the first-pass effect low. Oral administration resulted in peak plasma methotrexate concentrations of 8.4 +/- 0.5 mumol/l (382 +/- 23 microgram/100 ml) and was almost as effective as intravenous administration, which achieved peak concentrations of 9.9 +/- 0.4 mumol/l (450 +/- 18 microgram/100 ml). In all 14 patients the clinical response to oral treatment was comparable to that reported to intravenous administration of high-dose methotrexate used in combination with other cytotoxic drugs. The disease-free interval in cases of adult sarcoma was 7.4 +/- 1.3 months and the relapse rate 29%. Out of four patients with small-cell carcinoma, two showed an objective response to oral treatment. We suggest that oral high-dose methotrexate given in divided doses is a rational alternative to expensive intravenous high-dose methotrexate regimens, but further clinical evaluation is necessary.

Administration, Oral↗

PubMed2004

Methotrexate loaded SAE coated coronary stents reduce neointimal hyperplasia in a porcine coronary model.

OBJECTIVE: To evaluate the effect of stent based methotrexate delivery on neointimal hyperplasia. METHODS: Stainless steel coronary stents and biological polymer coated (SAE) stents were randomly implanted in coronary arteries of pigs with a stent to artery ratio of 1.1:1. The pigs were killed after five days (10 stents) or four weeks (20 stents). Second, stainless steel coronary stents were dip coated in a 10 mg/ml methotrexate-SAE polymer solution, resulting in a total load of 150 microg methotrexate/stent. SAE coated stents and methotrexate loaded stents were randomly implanted in porcine coronary arteries with a stent to artery ratio of 1.2:1 and followed up to four weeks. RESULTS: SAE coated stents and bare stents elicited a similar tissue response at five days. At four weeks, neointimal hyperplasia induced by the coated stents was less pronounced than with the bare stents (1.32 (0.66) v 1.73 (0.93) mm2, p > 0.05). In vitro drug release studies showed that 50% of the methotrexate was released in 24 hours, and all drug was released within four weeks. No impact on vascular smooth muscle cell proliferation or viability was observed in in vitro cell cultures. At four weeks the arteries with methotrexate loaded stents had decreased peristrut inflammation and neointimal hyperplasia (1.22 (0.34) v 2.25 (1.28) mm2, p < 0.01). CONCLUSIONS: SAE coating had an excellent biocompatibility with vascular tissue. Stent based delivery of methotrexate in the SAE coating effectively reduced neointimal hyperplasia in a porcine coronary stent model, potentially due to reduced peristrut inflammation.

Animals↗

PubMed1986

The effects of hypoxanthine on methotrexate-induced differentiation of cultured human choriocarcinoma (BeWo) cells.

When cultured human choriocarcinoma (BeWo) cells are exposed to methotrexate, proliferation ceases and cells undergo a complex differentiative response that resembles development of normal trophoblast. Although thymidylate starvation has been shown to be causative in methotrexate-induced expression of syncytiotrophoblastic markers by BeWo cells, the role of purine deprivation is uncertain since previous studies utilized growth media containing exogenous purines. This work investigated the effects of hypoxanthine on methotrexate-induced cell enlargement, expression of placental alkaline phosphatase, and morphological differentiation to the syncytiotrophoblast-like phenotype. When methotrexate exposures (1 microM, 48 h) were conducted in a purine-free basal medium supplemented with dialyzed fetal bovine serum, RNA synthesis was greatly reduced and cell enlargement did not occur. Specific methods for removing purines (charcoal extraction and xanthine oxidase treatment) decreased the ability of serum to support cell enlargement during methotrexate exposures, whereas addition of hypoxanthine to culture fluids restored its ability to support maximal increases in cell mass, confirming that purines were the factors lost during dialysis. In contrast, morphologically differentiation to the syncytiotrophoblast-like phenotype and increased expression of placental alkaline phosphatase were unaffected by the availability of purines during exposure to methotrexate.

Alkaline Phosphatase↗

PubMed1997

Methotrexate potentiates bradykinin-induced increase in macromolecular efflux from the hamster oral mucosa.

The purpose of this study was to determine whether methotrexate modulates bradykinin-induced increase in macromolecular efflux from the in situ oral mucosa and whether this response is mediated by the L-arginine/nitric oxide biosynthetic pathway. Using intravital microscopy, we found that suffusion of methotrexate alone onto the hamster cheek pouch had no significant effects on leaky site formation and increase in clearance of fluorescein isothiocyanate-labeled dextran (molecular mass, 70 kDa). However, methotrexate significantly potentiated bradykinin-induced responses (P < 0.05). These effects were associated with significant increases in nitrites concentration and guanosine 3',5'-cyclic monophosphate-like immunoreactivity in the suffusate and were abrogated by N(G)-nitro-L-arginine methyl ester (L-NAME) but not N(G)-nitro-D-arginine methyl ester (D-NAME). L-Arginine, but not D-arginine, abolished L-NAME-induced responses. ZnCI2 and indomethacin had no significant effects on methotrexate-induced responses. Methotrexate had no significant effects on adenosine- and ionomycin-induced increases in macromolecular efflux. Collectively, these data indicate that methotrexate amplifies bradykinin-induced increase in macromolecular efflux from the in situ oral mucosa in a specific, receptor- and L-arginine/nitric oxide biosynthetic pathway-dependent fashion.

Adenosine↗

PubMed2005

Severe encephalopathy induced by the first but not the second course of high-dose methotrexate mirrored by plasma homocysteine elevations and preceded by extreme differences in pretreatment plasma folate.

Plasma homocysteine has recently been associated with the occurrence of methotrexate-related neurotoxicity. We observed extreme elevations of homocysteine in a 9-year-old boy presenting with leukemia treated with the ALL-BFM 95 protocol. Coma occurred at about the 71st hour from the first methotrexate administration, and lasted for 30 h but MRI and CT studies showed no intracranial pathology. The second course of high-dose methotrexate was administered with no complications. Homocysteine areas under the curve (AUC) were calculated as the sum of areas of rectangles during the 6-hour intervals from T(0) to T(72) hours (AUC(0--72)) and methotrexate AUCs were evaluated using MW/PHARM 3.3 software. The AUC of homocysteine during the first, toxic course was 5.2 times higher than AUC during the second administration, whereas AUC of methotrexate also differed by a factor of 5. Plasma concentrations of folate prior to the first and the second courses, respectively, were 4.4 versus 45 micromol/l making this difference the most striking discriminator between the two courses. Mutation analysis showed that the patient was heterozygous for the C 677 T mutation in the MTHFR gene. We suggest that plasma homocysteine, pretreatment plasma folate and possibly the presence of MTHFR mutations may be biomarkers of methotrexate toxicity and possibly its antifolate effect targeted towards the tumor as well.

Antimetabolites, Antineoplastic↗

PubMed1969

Treatment of leukemia with large doses of methotrexate and folinic acid: clinical-biochemical correlates.

Patients with acute leukemia were given repeated cycles consisting of infusions of methotrexate followed by "rescue" with folinic acid. Peripheral blood leukemic cells were harvested from patients before cyclical treatment, and the rates of incorporation of thymidine and of deoxyuridine into deoxyribonucleic acid (DNA) were measuared in vitro. There was no relationship between the pretreatment incorporation of either deoxynucleoside into DNA and the clinical response to therapy. Methotrexate suppressed deoxyuridine incorporation into DNA by the leukemic blasts in vitro, but the patients whose cells were most sensitive to this effect did not necessarily go into remission when treated. Leukemic cells were sampled during methotrexate infusions and the deoxynucleoside incorporation rates were determined. Thymidine incorporation into DNA was variably affected. If, by the end of the first infusion, it remained elevated, remission rarely followed, whereas if it was below the pretreatment value, remission was much more likely. In all cases, deoxyuridine incorporation was suppressed during the infusion. The greatest suppression occurred in patients who went on to remission, but the suppression did not correlate with that expected from pretreatment in vitro tests unless due weight was given to the concomitant effects of the methotrexate therapy on thymidine incorporation. Leukemic blasts surviving successive cycles of therapy became progressively more resistant to the suppressing effects of methotrexate in vitro. This resistance became especially marked in the blasts of patients who did not go into remission. During methotrexate infusions, inhibition of leukemic cell dihydrofolate reductase activity was greatest in blasts of patients whose disease subsequently remitted.

Adolescent↗

PubMed1993

The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation.

Methotrexate, a folate antagonist, is a potent antiinflammatory agent when used weekly in low concentrations. We examined the hypothesis that the antiphlogistic effects of methotrexate result from its capacity to promote intracellular accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) that, under conditions of cell injury, increases local adenosine release. We now present the first evidence to establish this mechanism of action in an in vivo model of inflammation, the murine air pouch model. Mice were injected intraperitoneally with either methotrexate or saline for 3-4 wk during induction of air pouches. Pharmacologically relevant doses of methotrexate increased splenocyte AICAR content, raised adenosine concentrations in exudates from carrageenan-inflamed air pouches, and markedly inhibited leukocyte accumulation in inflamed air pouches. The methotrexate-mediated reduction in leukocyte accumulation was partially reversed by injection of adenosine deaminase (ADA) into the air pouch, completely reversed by a specific adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), but not affected by an adenosine A1 receptor antagonist, 8-cyclopentyl-dipropylxanthine. Neither ADA nor DMPX affected leukocyte accumulation in the inflamed pouches of animals treated with either saline or the potent antiinflammatory steroid dexamethasone. These results indicate that methotrexate is a nonsteroidal antiinflammatory agent, the antiphlogistic action of which is due to increased adenosine release at inflamed sites.

Adenosine↗

PubMedDate not supplied

Reversibility of elemental liquid diet-enhanced methotrexate toxicity by refeeding with chow.

The toxic effects of methotrexate administration [20 mg/kg, bolus intraperitoneally (ip)] to rats fed a regular chow diet (n = 10) was compared with results in animals fed an elemental, chemically defined, liquid diet (n = 10) for 7 days. All animals receiving an elemental diet became anorectic and lethargic within 60 hr of methotrexate injection. All animals in this group subsequently developed enteritis and died within 150 hr. There was no clinical evidence of enteritis in rats fed a regular chow diet and mortality as zero in this group (p less than 0.001). In a second study one group of rats (n = 9) was fed a regular chow diet for 7 days; four groups were fed an elemental, chemically defined, liquid diet (n = 9 per group) for 7 days. At 24 hr and 8 hr prior to, or 24 hr after methotrexate administration, one group was refed a regular chow diet; the fourth group was maintained on an elemental liquid diet throughout the study period. All rats fed a regular chow diet survived following methotrexate injection (20 mg/kg, ip). All rats fed an elemental diet throughout the study period died. Those rats refed a regular diet 24 or 8 hr prior to methotrexate injection demonstrated a significant improvement in survival (100% in the 24-hr group, 55% in the 8-hr group). However, those animals refed a regular diet 24 hr after methotrexate injection demonstrated a 100% mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Effect of protein-calorie malnutrition on methotrexate pharmacokinetics.

Methotrexate toxicity is increased in protein-calorie malnutrition. The influence of protein-calorie malnutrition on the pharmacokinetics and binding of methotrexate (MTX) and the formation of its major hepatic metabolite, 7-hydroxy-methotrexate was examined in 30 adult, female Lewis rats. Animals were randomized to receive either a standard diet (22.0% protein; 4.20 kcal/g) or a protein-depleted diet (PD) (0.03% protein; 4.27 kcal/g) ad libitum for 35 days. Animals were then separated into two groups for either methotrexate pharmacokinetics (n = 20) or serum protein binding (n = 10) studies. The mean weight loss in the PD group was 26% of their initial body weight, as compared with a 29% weight gain in the control group. In the protein binding study, a significant decrease in serum albumin (19%), uncorrected creatinine clearance (38%), and free fraction of MTX (15%) was found in the PD group. All animals in the pharmacokinetic study received a single intraperitoneal injection of MTX (10 mg/kg), and serum MTX and 7-hydroxy-methotrexate concentrations were determined using a specific, reversed phase, high-performance liquid chromatography assay. The mean AUC0-3 in the PD group was 43.6 +/- 3.9 micrograms/mL per hour compared with 15.8 +/- 1.1 micrograms/mL per hour in the control group (p < .001). The time to peak and the peak serum concentrations were significantly greater in the PD animals, which indicated delayed absorption and clearance. These results suggest that the increase in MTX toxicity observed in protein-calorie malnutrition is associated with a decrease in MTX clearance, and is not related to changes in protein binding or formation of 7-hydroxy-methotrexate.

Animals↗

PubMedDate not supplied

Methotrexate should not be used for patients with end-stage kidney disease.

Methotrexate is a widely used disease-modifying anti-rheumatic drug. Its effectiveness has been proven in placebo-controlled trials and in comparison with other disease-modifying anti-rheumatic drugs. The pharmacokinetics of methotrexate are highly variable and unpredictable. In patients with normal renal function, the recommended dose in rheumatoid arthritis ranges between 7.5 and 15 mg/week, but in recent years, even dosages up to 25 mg weekly are used. Toxicity includes myelosuppression, gastrointestinal adverse effects, hepatotoxicity and pneumonitis. Renal impairment and age are considered major risk factors for developing methotrexate toxicity, but studies show conflicting results. Whether methotrexate can be administered to patients with end-stage kidney disease has not been formally tested. The present case illustrates the severe side effects of low-dose methotrexate treatment in a patient with end-stage kidney disease. Seven other cases have reported similar and even more severe and irreversible consequences after low-dose regimen. In view of these side effects we strongly recommend to monitor toxicity rigorously in patients with stage 3 or stage 4 kidney disease and not to use methotrexate in patients with stage 5 kidney disease.

Aged↗

PubMed1977

Comparison of intra-articular methotrexate with intra-articular triamcinolone hexacetonide by thermography.

A comparison of intra-articular methotrexate and intra-articular triamcinolone hexacetonide was made in 42 arthritic patients with persistent bilateral knee effusions. One knee was injected with either 5 mg methotrexate (two injections of 2.5 mg a week apart) or a single injection of 20 mg triamcinolone. An objective assessment of both knees was made by quantitative thermography at 0,3,7,14 and 21 days. Joints injected with triamcinolone showed a greater fall in thermographic index (T.I) than the joints injected with methotrexate, which showed similar change to the non-injected knee joints in both groups. Four patients received larger doses of methotrexate, up to 20 mg, though the fall in T.I. was still less than the mean fall for triamcinolone injected joints. Peak venous blood levels of methotrexate were reached 1 hour after intra-articular injection, and a sphygmomanometer cuff inflated around the leg above the injected knee for periods of up to 1 hour did not appreciably delay this. Methotrexate had no immediate anti-inflammatory effect, even in psoriatic arthropathy, and did not give the relief of intra-articular steroid.

Adult↗

PubMed1985

Remission induction of meningeal leukemia with high-dose intravenous methotrexate.

Twenty children with acute lymphoblastic leukemia who developed meningeal disease were treated with a high-dose intravenous methotrexate regimen that was designed to achieve and maintain CSF methotrexate concentrations of 10(-5) mol/L without the need for concomitant intrathecal dosing. The methotrexate was administered as a loading dose of 6,000 mg/m2 for a period of one hour followed by an infusion of 1,200 mg/m2/h for 23 hours. Leucovorin rescue was initiated 12 hours after the end of the infusion with a loading dose of 200 mg/m2 followed by 12 mg/m2 every three hours for six doses and then every six hours until the plasma methotrexate level decreased to less than 1 X 10(-7) mol/L. The mean steady-state plasma and CSF methotrexate concentrations achieved were 1.1 X 10(-3) mol/L and 3.6 X 10(-5) mol/L, respectively. All 20 patients responded to this regimen, 16/20 (80%) achieved a complete remission, and 20% obtained a partial remission. The most common toxicities encountered were transient serum transaminase and bilirubin elevations, neutropenia, and mucositis. One patient had focal seizures and transient hemiparesis but recovered completely. High-dose intravenous methotrexate is an effective treatment for the induction of remission after meningeal relapse in acute lymphoblastic leukemia.

Adolescent↗

PubMed1985

Curability of Burkitt's lymphoma with high-dose cyclophosphamide-high-dose methotrexate therapy and intrathecal chemoprophylaxis.

Twenty-four children with Burkitt's lymphoma were treated beginning May 1976 with a regimen alternating high doses of cyclophosphamide and methotrexate in induction and consolidation; only high doses of methotrexate were used in the maintenance phase. Throughout therapy, which was planned for 54 weeks, intrathecal chemoprophylaxis using methotrexate, cytosine arabinoside, and hydrocortisone was coordinated with the high-dose methotrexate infusion therapy to provide CNS chemoprophylaxis that maintained therapeutic methotrexate spinal fluid levels (greater than 10(-6) mol/L) for approximately 60 hours. Twenty-two (92%) of the 24 children attained complete remission; two (8.3%) patients attained only partial remission, failing therapy. Two children died of infection while in complete remission; two children relapsed on therapy. Actual survival is 75%; the median follow-up time is 38+ months (range, 1 1/2+ to 84+ months). Relapses correlated with Murphy disease stage as follows: stage I--0/3, stage II--2/7, stage III--2/10, and stage IV--0/2. Serious side effects and toxicities of chemotherapy occurred in ten patients (metabolic disturbances after rapid tumor lysis, two; infectious and/or febrile episodes following cyclophosphamide therapy, three; methotrexate side effects, four; and complications of intrathecal therapy, one). Results of this therapy are similar to those of the best regimens that have been reported. Treatment has been adapted for use in Burkitt's lymphoma by the Pediatric Oncology Group; the responsiveness of other B cell lymphomas of childhood to this treatment is also being determined.

Adolescent↗

PubMed1989

Selective intraperitoneal biochemical modulation of methotrexate by dipyridamole.

Dipyridamole increases the toxicity of methotrexate in a concentration-dependent manner. We hypothesized that concurrent intraperitoneal administration of both drugs would result in high peritoneal concentrations with much lower plasma concentrations, permitting a selective increase in the activity of methotrexate against intraperitoneal tumors without enhancing systemic toxicity. Initially, 2.16 mg/m2/d methotrexate and 12 mg/m2/d dipyridamole were delivered together as a constant intraperitoneal infusion for 48 hours. With escalation of chemotherapy, eventually 4.32 mg/m2/d methotrexate was administered for 168 hours. Forty-seven courses were administered to 18 patients. The mean peritoneal to plasma concentration ratios of methotrexate and non-protein bound dipyridamole were 71.6 +/- 34.8 and over 2,300, respectively. Chemical peritonitis was the dose-limiting toxicity. Three patients had some evidence of a response (two with decreasing tumor markers, and the third with a reduction in ascites). We conclude that the drug concentrations are in an appropriate range for selective intraperitoneal biochemical modulation of methotrexate, and that it is feasible to expose tumors confined to the peritoneal cavity to these drugs for long periods of time.

Adult↗

PubMed1993

Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group.

PURPOSE: This prospective randomized cooperative group study was conducted in patients with neoplastic meningitis treated with intrathecal methotrexate or thiotepa to assess response rates and survival, prognostic factors, and the toxicity of these regimens. PATIENTS AND METHODS: Fifty-nine adults with nonleukemic malignancies, performance status of 0 to 3, and positive CSF cytologies were assigned to receive intrathecal methotrexate (10 mg) or thiotepa (10 mg) twice weekly. Radiation, was administered to mass lesions and/or symptomatic sites and appropriate systemic therapy was given concomitantly. RESULTS: Fifty-two patients were assessable. Most were female (79%), nonambulatory (77%), had been pretreated with radiation (52%) and chemotherapy (77%), and had evidence of systemic disease (65%). Most primary cancers were of the breast (48%), lung (23%), or lymphatics (19%). Treatment arms were well balanced, except that more patients randomized to methotrexate had breast cancer (61% v 33%) and were without evidence of systemic cancer (21% v 4%). No patient had important neurologic improvement with therapy, and 75% deteriorated neurologically within 8 weeks of initiating therapy. Survival ranged from 4 days to 110.5+ weeks. Median survival for patients receiving methotrexate was 15.9 weeks and 14.1 weeks for patients treated with thiotepa. Factors predictive of shorter survival included progressive systemic disease (P = .0005), poor performance status (P = .03), and significant cranial nerve palsies (P = .02). Although serious toxicities were similar, mucositis (P = .04) and neurologic complications (P = .008) were more common in patients who received methotrexate. CONCLUSION: The efficacy and overall toxicities of intraventricular methotrexate and thiotepa seem similar and neither reverses fixed neurologic deficits. Early diagnosis and treatment and new therapeutic approaches are needed to improve the outcome for patients with neoplastic meningitis.

Aged↗

PubMed1995

Changes of cerebral biopterin and biogenic amine metabolism in leukemic children receiving 5 g/m2 intravenous methotrexate.

Acute or subacute neurologic disorders can be observed in patients receiving high-dose methotrexate therapy for lymphoblastic leukemia or malignant tumor. Impairment of biopterin metabolism leading to decreased availability of monoamine neurotransmitters has been suggested to explain methotrexate neurotoxicity. To investigate such a mechanism, we have measured prospectively by HPLC the concentrations of total biopterin, homovanillic acid, and 5-hydroxyindolacetic acid in cerebrospinal fluid of 57 children with acute lymphoblastic leukemia. A sequential analysis of cerebrospinal fluid was performed for each patient: cerebrospinal fluid samples were obtained before therapy and after each of the four high-dose methotrexate infusions during the CNS prophylaxis phase. A significant increase of total biopterin concentrations in cerebrospinal fluid was observed after high-dose methotrexate therapy compared with the pretreatment values. No cumulative effect was noted. In contrast, no significant variation of the homovanillic acid and 5-hydroxyindolacetic acid levels was observed in cerebrospinal fluid. However, individual analysis revealed a transient decrease of homovanillic acid and 5-hydroxyindolacetic acid concentrations in cerebrospinal fluid of six children. The increase of total biopterin mimicking that observed in inherited dihydropteridine reductase deficiencies suggests that methotrexate inhibits the regenerating system of biopterin in the brain of patients undergoing high-dose methotrexate therapy.

Adolescent↗

PubMed2000

Treatment of persistent rejection with methotrexate in stable patients submitted to heart transplantation.

OBJECTIVE: To evaluate the use of methotrexate for the treatment of recurrent rejection in heart transplant recipients. METHODS: We studied 6 patients submitted to heart transplantation that showed rejection grade >/= 3A (ISHLT) in two consecutive endomyocardial biopsy specimens. The dose was 11.26+/-3.75 mg/week. The evaluated data were: ventricular function, endomyocardial biopsy, white cell count and number of rejection episodes before and after methotrexate administration. RESULTS: There was a reduction in the number of rejection episodes (5.17+/-1.47 before methotrexate; 2.33+/-1.75 after 6 months and 3.17+/-2.99 after 12 months of treatment, p=0. 0193). The ventricular function was normal with ejection fraction of 76.5+/-4.80 before and 75.6+/-4.59 after methotrexate (p=0.4859). One patient did not finish the treatment because he showed signs of rejection associated with severe pericardial effusion. Five patients had a reduction in the white cell count (8,108+/-23.72 before and 5650+/-1350 after methotrexate, p=0.0961). One pulmonary infection with complete resolution after antibiotic treatment was observed. CONCLUSION: Methotrexate in low doses is an effective adjunct therapy in the treatment of recurrent rejection after heart transplantation.

Adolescent↗

PubMed2004

Methotrexate-loxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3.

Human organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8) are responsible for renal tubular secretion of an antifolic acid methotrexate, and are considered to be involved in drug interaction of methotrexate with nonsteroidal anti-inflammatory drugs (NSAIDs). In our hospital, a delay of methotrexate elimination was experienced in a patient with Hodgkin's disease, who took loxoprofen, a commonly used NSAID in Japan, which suggested a cause. In this study, we examined the drug interaction via hOAT1 and hOAT3, using Xenopus laevis oocytes. hOAT1 and hOAT3 mediated the methotrexate transport with low affinity (K(m) of 724.0 muM) and high affinity (K(m) of 17.2 muM), respectively. Loxoprofen and its trans-OH metabolite, an active major metabolite, markedly inhibited the methotrexate transport by both transporters. Their inhibition concentrations (IC(50)) were in the range of the therapeutic levels. These findings suggest that loxoprofen retards the elimination of methotrexate, at least in part, by inhibiting hOAT1 and hOAT3.

Animals↗