Methotrexate disposition following concomitant administration of ketoprofen, piroxicam and flurbiprofen in patients with rheumatoid arthritis.

Abstract

The effects of three non-steroidal anti-inflammatory drugs (NSAIDs) on the pharmacokinetics of methotrexate were studied in 10 patients with rheumatoid arthritis.Ketoprofen (3 mg kg-' day-'), flurbiprofen (3 mg kg-' day-'), piroxicam (20 mg day-') or a non-NSAID control (paracetamol/acetaminophen) were administered to patients for at least 6 days (13 days in the case of piroxicam to establish steady state) in a randomized crossover design prior to receiving a weekly oral dose of methotrexate. In the non-NSAID control portion of the study, MTX oral clearance (CLo) was 11.0 ± 3.9 1 h-', renal clearance (CLR) was 7.9 ± 2.8 1 h-1, percent

Four-year experience with methotrexate exposures

“…At doses Ͻ30 mg/m 2 , MTX is generally absorbed with a mean bioavailability of about 60-70%. However, at doses approaching 80 mg/m 2 , absorption is as low as 20%, most likely due to enzyme saturation [8,9].…”

“…In 1991, an 80-year-old woman was reported to have mistakenly ingested 10 mg of MTX for 4 consecutive days, resulting in mucositis, fever and pancytopenia but, again, no long-term injury [7]. Chronic overdose can result in death [8,9].…”

Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis

“…More recently, combinations of methotrexate with other second-line agents (sulfasalazine, hydroxychloroquine, anti-tumor necrosis factor agents, and other biologicals) have been reported to have greater efficacy than methotrexate alone without greater toxicity (O'Dell et al, 1996(O'Dell et al, , 2002Maini et al, 1998;Lipsky et al, 2000;Ferraccioli et al, 2002;Hochberg et al, 2003;Schroder et al, 2004;St Clair et al, 2004). Nonsteroidal anti-inflammatory agents modestly diminish renal clearance of methotrexate and its major metabolite 7-hydroxymethotrexate, although this interaction is generally not clinically significant Weinblatt, 1989;Stewart et al, 1990Stewart et al, , 1991Tracy et al, 1992Tracy et al, , 1994. Hydroxychloroquine alters the pharmacokinetics of methotrexate; there is slower clearance and uptake with a greater area under the curve for methotrexate in patients taking the combination (Carmichael et al, 2002), and this interaction may account for the greater efficacy of the combination of hydroxychloroquine and methotrexate than methotrexate alone (O'Dell et al, 2002).…”

Increasing Systemic Exposure of Methotrexate by Active Efflux Mediated by Multidrug Resistance-Associated Protein 3 (Mrp3/Abcc3)

“…Methotrexate (N-{4-[(2,4-diaminopteridin-6-ylmethyl)-(methyl)amino]benzoyl}-L-glutamic acid), an inhibitor of dihydrofolate reductase, has been used clinically to treat neoplastic and autoimmune diseases including rheumatoid arthritis and psoriasis. Methotrexate is well absorbed from the small intestine into the systemic circulation (Tracy et al, 1994) followed by excretion into the urine in the unchanged form in humans (Egan et al, 1999). The accumulated evidence thus far suggests that multiple transporters are involved in the disposition of methotrexate.…”

“…Proton-coupled folate transporter (PCFT)/SLC46A1 (Nakai et al, 2007) and reduced folate carrier (RFC)-1 (Said et al, 1996) are involved in folate uptake from the intestinal lumen via the brush border membrane. For renal elimination of methotrexate, which involves tubular secretion as well as glomerular filtration (Tracy et al, 1994), organic anion transporter (Oat)-3/ Slc22a8 mediates uptake into the kidney via the basolateral membrane of the proximal tubules (Nozaki et al, 2004;VanWert and Sweet, 2008), and subsequent luminal efflux in the kidney is mediated by multiple ABC transporters, such as breast cancer resistance protein (Bcrp)/Abcg2 in rodents (Breedveld et al, 2004) and MRP2/ABCC2 in humans (Rau et al, 2006;Nozaki et al, 2007). In rodents, although methotrexate is predominantly excreted in the unchanged form as in humans, biliary excretion makes a greater contribution than urinary excretion (Masuda et al, 1997;Breedveld et al, 2004).…”