The effects of antibiotics and uricosuric drugs on the renal elimination of methotrexate and 7-hydroxymethotrexate in rabbits

Iven, H.; Brasch, Helmut

doi:10.1007/bf00264201

Cited by 21 publications

(8 citation statements)

References 24 publications

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“…The functional activities of MRP2 and FBP1 have been demonstrated to affect the elimination of MTX. For instance, high plasma concentrations, a long half-life, and slow clearance of MTX were observed in MRP2-deficient patients (Hulot et al, 2005) and in EHBR (Masuda et al, 1997), and in the presence of the Mrp2 inhibitors probenecid (Iven and Brasch, 1988;Ueda et al, 2001) and penicillin G (Iven and Brasch 1990). Increased renal clearance of MTX was observed in the presence of cephalosporins, ceftriaxone, sulfamethoxazole, indomethacin, and flurbiprofen Brasch, 1988, 1990;Statkevich et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Effect of DPC 333 [(2R)-2-{(3R)-3-Amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide], a Human Tumor Necrosis Factor α-Converting Enzyme Inhibitor, on the Disposition of Methotrexate: A Transporter-Based Drug-Drug Interaction Case Study

Luo

Garner

Xiong³

et al. 2007

Drug Metab Dispos

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DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide]is a potent human tumor necrosis factor ␣-converting enzyme inhibitor with potential therapeutic implications for rheumatoid arthritis. Methotrexate (MTX), a drug for the treatment of rheumatoid arthritis, is eliminated primarily unchanged via renal and biliary excretion in humans as well as in rats and dogs. The objective of the present study was to investigate the potential effect of DPC 333 on the disposition of MTX. In dogs, DPC 333 administered orally at 1.7 mg/kg 15 min before the intravenous administration of [ MTX, a bicarboxylic acid (Fig. 1) structurally similar to folic acid, has been used for the treatment of rheumatoid arthritis at low doses (Weinblatt et al., 1985;Schnabel and Gross, 1994). MTX is minimally metabolized to 7-hydroxy MTX in vivo, whereas most MTX is eliminated as intact drug via renal and biliary excretion in humans (Henderson et al., 1965b;Lui et al., 1985;Nuernberg et al., 1990;Seideman et al., 1993;Chladek et al., 1998), and in the preclinical species including mice, rats, dogs, and monkeys (Henderson et al., 1965a;Steinberg et al., 1982;Masuda et al., 1997). In mice and rats, the routes of biliary and renal elimination contribute almost equally to the total body clearance of MTX, but in monkeys and humans, renal elimination is more extensive than biliary excretion (Henderson et al., 1965a,b;Steinberg et al., 1982;Williams and Huang, 1982;Nuernberg et al., 1990;Masuda et al., 1997). For example, after intravenous administration, the cumulative biliary excretion of MTX was 44 to 72% of the dose in bile duct-cannulated rats, but only 16% in rhesus monkeys with bile fistula; after intraperitoneal or intravenous administration, MTX recovery in feces was 45% of the dose in rats and 40% in mice, but only 13% in monkeys and 10% in humans. Biliary H.X. and K.L.R.B. were funded in part by Grant R01 GM41935 from the National Institutes of Health.Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

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Section: Discussionmentioning

confidence: 99%

Effect of DPC 333 [(2R)-2-{(3R)-3-Amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide], a Human Tumor Necrosis Factor α-Converting Enzyme Inhibitor, on the Disposition of Methotrexate: A Transporter-Based Drug-Drug Interaction Case Study

Luo

Garner

Xiong³

et al. 2007

Drug Metab Dispos

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“…Excretion of MTX is inhibited by weak organic acids such as aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), piperacillin, penicillin G, and probenicid (9). Cephalosporins may also inhibit renal excretion, probably by competition for tubular secretion (86). A single recent publication indicates that hydroxychloroquine appears to enhance the effects of MTX by increasing the area under the curve for MTX concentration time by an average of 65% (87).…”

Section: Renal Excretionmentioning

confidence: 99%

Toward a better understanding of methotrexate

Kremer¹

2004

Arthritis & Rheumatism

260

177

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“…It has been established that 50-90% of each dose of methotrexate (MTX) is excreted by the kidney as an unchanged drug [1][2][3]. Renal impairment has been re ported in patients treated with high-dose MTX [4][5][6], However, these reports have not been substantiated with histological studies.…”

Section: Introductionmentioning

confidence: 71%

Nephrotoxicity of Low-Dose Methotrexate in Guinea Pigs: An Ultrastructural Study

Ma²,

Hm³

et al. 1996

Nephron

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The nephrotoxicity of low-dose methotrexate (MTX) and the rescue effect of leucovorin were studied by electron-microscopic examination of the kidney of guinea pigs. One group received MTX as a single weekly dose of 10 mg/kg, i.p.; a second group received a similar dose divided into three equal fractions. The third group received MTX rescued with an equal dose of leucovorin. The distal convoluted tubule showed cell swelling, fragmentation of the endoplasmic reticulum and loss of mitochondrial cristae and matrix. Leucovorin minimized these changes. The proximal tubule and the glomerulus were not affected. Low-dose MTX induced a nephrotoxicity in the distal convoluted tubule which could be minimized by leucovorin. Mild myelosuppression was also observed.

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The effects of antibiotics and uricosuric drugs on the renal elimination of methotrexate and 7-hydroxymethotrexate in rabbits

Cited by 21 publications

References 24 publications

Effect of DPC 333 [(2R)-2-{(3R)-3-Amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide], a Human Tumor Necrosis Factor α-Converting Enzyme Inhibitor, on the Disposition of Methotrexate: A Transporter-Based Drug-Drug Interaction Case Study

Effect of DPC 333 [(2R)-2-{(3R)-3-Amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide], a Human Tumor Necrosis Factor α-Converting Enzyme Inhibitor, on the Disposition of Methotrexate: A Transporter-Based Drug-Drug Interaction Case Study

Toward a better understanding of methotrexate

Nephrotoxicity of Low-Dose Methotrexate in Guinea Pigs: An Ultrastructural Study

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