Total and Free Methotrexate Pharmacokinetics, With and Without Piroxicam, in Rheumatoid Arthritis Patients

Combe, Bernard; Edno, L.; Lafforgue, P.; Bologna, C; Bernard, J.-C.; Acquaviva, P; Sany, J; Bressolle, Françoise

doi:10.1093/rheumatology/34.5.421

Cited by 56 publications

(48 citation statements)

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“…The in vitro plasma protein binding study revealed that 38-43% of MTX was in bound form. This is in agreement with a previous study that showed plasma protein binding in the range of 25 to 55% (Combe et al, 1995). The conjugate exhibited 36-42% of plasma protein binding (Supplementary file).…”

Section: Lipophilicity and Protein Bindingsupporting

confidence: 93%

Development and characterization of lysine-methotrexate conjugate for enhanced brain delivery

Singh

Subudhi

2014

Drug Delivery

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Background information: Methotrexate (MTX), an anticancer drug of choice, has poor permeability across blood-brain barrier (BBB) making it unsuitable for brain tumor application. Its brain availability and scope of application was improved by preparation of reversible conjugate with lysine by capitalizing the endogenous transport system of lysine at BBB. Methods: To enhance its delivery to brain, MTX was reversibly conjugated with L-Lysine by an amide linkage. It was characterized by advanced spectroscopy techniques including IR, NMR and MS. Furthermore, conjugate was assessed for stability, toxicity and drug release ability. In vivo distribution studies were done by radioscintigraphy study using 99m Tc radioisotope. Results: The structure of prodrug was confirmed by

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Section: Lipophilicity and Protein Bindingsupporting

confidence: 93%

Development and characterization of lysine-methotrexate conjugate for enhanced brain delivery

Singh

Subudhi

2014

Drug Delivery

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“…Adjunctive drugs may modify MTX absorption and metabolism; previous studies showed that steroids and some types of NSAID modify the pharmacokinetics of intramuscularly administrated MTX. [14][15][16] In the present study, no modifi cations in MTX pharmacokinetics caused by coadministered steroids or NSAIDs were observed. However, as there are manifold combinations of factors, it is diffi cult to evaluate the effects of coadministered drugs to MTX pharmacokinetics in a clinical setting.…”

Section: Discussionmentioning

confidence: 71%

Higher maximal serum concentration of methotrexate predicts the incidence of adverse reactions in Japanese rheumatoid arthritis patients

et al. 2007

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Weekly pulsed low-dose methotrexate (MTX) is a standard regimen for rheumatoid arthritis (RA). Severe adverse reactions to MTX, such as pneumonia and cytopenia, sometimes occur; however, it is difficult to predict the development of these adverse reactions. In this article, we examine the serum concentrations of orally administered MTX of 69 Japanese patients with RA in the clinical setting. The maximum serum concentration (C (max)) after the first dose of the weekly administration and the time at which C (max) was obtained (T (max)) were analyzed. C (max) correlated with the administered dose before measurement. The average T (max) was 2.0 +/- 0.8 h, and none of the patients showed a T (max) of more than 4 h. In addition, we demonstrated that the weekly MTX dosage and the mean dosage of steroids were significantly higher in patients with adverse reactions than in those without them, and the C (max) after the first dose of the weekly administration particularly correlated with the incidence of adverse reactions (P < 0.001). In fact, the cut-off point of C (max) (0.16 micromol/l) was a sensitive predictor of the adverse reactions (sensitivity 81% and specificity 67%). We concluded that C (max) after the first dose of weekly administration is a useful parameter for predicting the development of adverse reactions to MTX.

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“…However, it has been reported that the pharmacokinetics of MTX are not modified by concomitant administration of diclofenac, piroxicam, naproxen, and ketoprofen 56 11 13 By contrast, Tracy et al reported a decrease in the systemic clearance of MTX in patients treated with naproxen 14. Kremer and Hamilton reported significant decreases in renal clearance of MTX but no change in total clearance when NSAIDs are taken with higher maintenance dose of MTX but not at a 7.5 mg maintenance dose 15…”

Section: Discussionmentioning

confidence: 99%

Effects of moderate renal insufficiency on pharmacokinetics of methotrexate in rheumatoid arthritis patients

Bressolle¹,

Bologna²,

Kinowski³

et al. 1998

Annals of the Rheumatic Diseases

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Objectives-To determine the eVects of impaired renal function on the pharmacokinetics of methotrexate (MTX) in rheumatoid arthritis (RA) patients. Methods-77 RA patients were included in this study. MTX was administered intramuscularly (7.5 to 15 mg). Subjects were divided into four groups, according to their creatinine clearance (CL CR ); group 1: CL CR lower than 45 ml/min; group 2: CL CR between 45 and 60 ml/min, group 3: CL CR between 61 and 80 ml/min and group 4: CL CR higher than 80 ml/min. Blood samples were collected from each subject before drug administration and at two and eight hours after administration. Individual pharmacokinetic parameters were estimated using a Bayesian approach. Results-MTX concentrations (total and free) were 1.3 to 1.6-times higher in group 1 than in groups 2, 3, and 4. For total and free MTX, t 1/2 eliminations were 22.7 hours in group 1, 13.5 hours in group 2, 12 hours in group 3, and 11 hours in group 4. Clearance of total MTX was 64, 92, 96, 115 ml/min in groups 1 to 4, respectively, it was 118, 163, 171, 206 ml/min in groups 1 to 4 for the free MTX, respectively. Volume of distribution averaged 2.16 l/kg in group 1, 1.92 l/kg in group 2, 1.61 l/kg in group 3, and 1.56 l/kg in group 4. Elimination half life was significantly increased and total clearance was significantly reduced with the degree of renal impairment. Linear regression revealed good correlations between clearance values of MTX and creatinine clearance. Conclusion-Individual testing is required rather than a general decrease of the MTX dose based only on CL CR .

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Total and Free Methotrexate Pharmacokinetics, With and Without Piroxicam, in Rheumatoid Arthritis Patients

Cited by 56 publications

References 0 publications

Development and characterization of lysine-methotrexate conjugate for enhanced brain delivery

Development and characterization of lysine-methotrexate conjugate for enhanced brain delivery

Higher maximal serum concentration of methotrexate predicts the incidence of adverse reactions in Japanese rheumatoid arthritis patients

Effects of moderate renal insufficiency on pharmacokinetics of methotrexate in rheumatoid arthritis patients

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