Metabolic studies of the effects of methotrexate (2023)

Cited by (24)

  • Associations between osteoporosis and drug exposure: A post-marketing study of the World Health Organization pharmacovigilance database (VigiBase®)

    2021, Bone

    Bone remodeling is a complex process, and many conditions (including drug exposure) lead to osteoporosis. Here, we sought to detect new disproportionality signals for drugs associated with osteoporosis.

    We performed a disproportionality analysis of the World Health Organization's VigiBase® pharmacovigilance database through April 12, 2020. The frequency of reports on osteoporosis for all identified drug classes was compared with that for all other drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval (CI)].

    Of the 7,594,968 cases spontaneously recorded to VigiBase®, 4758 concerned osteoporosis. New disproportionality signals with a pharmacologically plausible mechanism were found for drugs used in neurology (levodopa (ROR [95%CI]: 10.18 [4.33–25.10]), selective serotonin agonists (4.22 [2.34–7.00]) and memantine (4.10 [1.56–8.93])), hematology (romiplostim (4.93 [1.15–21.10])), pulmonology (macitentan (3.02 [1.84–4.90])), ophthalmology (ranibizumab (3.31 [1.00–10.51])) and rheumatology (tofacitinib (3.65 [3.00–4.40])). The robustness of these new results is supported by the significant RORs for the vast majority of drugs already known to induce osteoporosis and/or increase the fracture risk, namely glucocorticoids, gonadotropin-releasing hormone analogs, anti-aromatases, androgen receptor blockers, thyroid hormones, proton pump inhibitors, thiazolidinediones, vitamin K antagonists, loop diuretics, protease inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors, and enzyme-inducing antiepileptics including barbiturates and derivatives, hydantoin derivatives, carboxamide derivatives and fatty acid derivatives.

    We established up a comprehensive list of drugs potentially associated with osteoporosis and highlighted those with pharmacologically plausible mechanisms leading to bone fragility. Our results might pave the way for additional exploration of these mechanisms.

  • Osteoporosis Associated with Illnesses and Medications

    2013, Osteoporosis: Fourth Edition

    Primary osteoporosis is a condition characterized by global skeletal fragility that develops in association with the usual processes of menopause and advancing age. Secondary osteoporoses are the consequence of specific clinical disorders and medications, including a variety of endocrine, gastrointestinal, rheumatologic, and genetic diseases that cause low bone mineral density (BMD), either by interfering with attainment of peak bone mass or by increasing rates of involutional bone loss. In addition, many drugs are associated with alterations in bone remodeling that may lead tobone loss and/or impairment of bone strength. The effects of these diseases and drugs may be superimposed upon the primary processes that cause osteoporosis, exacerbating age- and menopause-related bone loss in affected individuals. In this chapter, we consider certain disorders and drugs that are frequently associated with osteoporosis. Those addressed here are indicated in boldface type in Table 48.1, whereas the table refers the reader to those covered elsewhere in this book by indicating the appropriate chapter in which they are considered. Some topics previously considered in this chapter, such as diabetes mellitus and anticonvulsant medications, now appear as stand-alone chapters elsewhere in this book.

  • Osteoporosis Associated with Illnesses and Medications

    2008, Osteoporosis, Two-Volume Set

  • Methotrexate maintains bone mass by preventing both a decrease in bone formation and an increase in bone resorption in adjuvant-induced arthritic rats

    1997, Bone

    (Video) Methotrexate Side Effects, Mechanism of Action, and Indications

    We examined the effects of low doses methotrexate (MTX) and indomethacin (IND) on bone mass and turnover in normal male Spraque-Dawley rats and those with adjuvant-induced arthritis. Normal and the adjuvant (heat-killed mycobacterium)-injected rats, 6 weeks of age, were given MTX at daily doses of 0.05, 0.1, or 0.2 mg/kg body weight (BW) or IND at a daily dose of 1.0 mg/kg BW. Rats were killed at the start, or at 14 and 28 days. In normal rats, the administration of these agents did not change the lumbar and femoral BMD values, nor did the serum osteocalcin or urinary deoxypyridinoline (D-Pyr) levels. Lumbar trabecular osteoclast number (Oc.N/BS) and osteoclast surface (Oc.S/BS) were decreased in the rats given IND. In the arthritic rats, the administration of MTX did not prevent an early increase of paw edema in the adjuvant-injected limb, but late inflammatory was alleviated in the non-injected limb. However, MTX administration at a dose of 0.1–0.2 mg/kg BW maintained an age-dependent increase in the lumbar and femoral BMD values. While serum osteocalcin levels were decreased and urinary D-Pyr values were increased in the arthritic control rats, these bone markers remained at the levels of the normal rats. Decreases in mineral apposition rate (MAR) and bone formation rate (BFR/BS) and increases in the trabecular Oc.N/BS and Oc.S/BS values were prevented by MTX. While IND almost completely prevented inflammatory paw edema, it did not improve the parameters of bone formation. An increase in osteoclasts was prevented and the osteopenia in the lumbar and the femoral bone was only partially prevented by IND. These data suggest that MTX improves bone mass and turnover in the arthritic rat, in which several cytokines that affect bone cells are involved. An increase in bone resorption may be due to prostaglandins, but bone formation defect was suggested to be due to other cytokines such as IL-1, II-6, and TNF-α in this model.

  • Methotrexate-the rapidly acting drug

    1990, Bailliere's Clinical Rheumatology

View all citing articles on Scopus

Recommended articles (6)

  • Research article

    Co-administration of a commonly used Zimbabwean herbal treatment (African potato) does not alter the pharmacokinetics of lopinavir/ritonavir

    International Journal of Infectious Diseases, Volume 17, Issue 10, 2013, pp. e857-e861

    African potato (Hypoxis obtusa) is commonly used in Sub-Saharan Africa as a complementary herbal remedy for HIV-infected patients. It is unknown whether or not co-administration of African potato alters the pharmacokinetics of protease inhibitor antiretrovirals. The objective of this study was to investigate the impact of the African potato on the steady-state pharmacokinetics of ritonavir-boosted lopinavir (LPV/r).

    Sixteen adult volunteers were administered LPV/r 400/100mg twice a day for 14 days, followed by concomitant administration with African potato given once daily for 7 days. Lopinavir plasma exposure as estimated by the area under the concentration–time curve over the 12-h dosing interval (AUC0–12h, AUCτ) was determined on day 14 and again on day 21. Lopinavir in plasma was analyzed using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Steady-state AUCτ and the maximum concentration following dose administration (Cmax) were determined using non-compartmental methods using WinNonlin Professional version 5.2.1. Statistical analyses were performed using Stata version 12.1.

    (Video) Side Effects of Methotrexate

    Co-administration of African potato was not associated with any change in lopinavir AUCτ, Cmax, or Ctrough.

    African potato when taken concomitantly with LPV/r is well-tolerated and not associated with clinically significant changes in lopinavir pharmacokinetics.

  • Research article

    The prediction roles of asymmetric dimethyl-arginine, adiponectin and apelin for macroangiopathy in patients with impaired glucose regulation

    Annales d'Endocrinologie, Volume 77, Issue 6, 2016, pp. 633-640

    To investigate the effects of asymmetric dimethyl-arginine (ADMA), adiponectin (APN) and apelin in predicting macroangiopathy in impaired glucose regulation (IGR) patients.

    A total of 210 patients undergoing oral glucose tolerance test were included in this study. They were classified to normal glucose tolerance (NGT, n=42), impaired fasting glucose (IFG, n=36), impaired glucose tolerance (IGT, n=92, including 44 IGT1 and 48 IGT2 patients) and IFG+IGT (n=40) groups. APN, apelin and ADMA levels, blood pressure, blood lipid, insulin, body mass index (BMI), and homeostasis model assessment of insulin resistance (HOMA-IR) were detected. The severity and extent of coronary atherosclerosis were determined by the Gensini score.

    The prevalence of coronary heart disease and Gensini scores in IGT and IFG+IGT groups were similar but both were higher than NGT and IFG groups (all P<0.05). Lower APN, higher ADMA and apelin levels were witnessed in IGT and IGT+IFG groups compared with NGT and IFG groups (all P<0.05). IGT2 group had higher 2-h PG and apelin levels and Gensini scores but lower APN levels than IGT1 group (all P<0.05). Gensini score was positively correlated with apelin (r=0.669) and ADMA (r=0.764), but were negatively correlated with APN (r=–0.555, all P<0.001). ADMA and APN were the independent factors affecting Gensini score.

    ADMA and APN levels could be predictive factors for macroangiopathy in IGR patients, especially in IGT cases.

    Étudier le rôle de la diméthyl-arginine asymétrique (ADMA), de l’adiponectine (APN) et l’apeline dans la prédiction de macroangiopathie chez des patients souffrant de troubles de la glycémie.

    Un total de 210patients soumis à un test de tolérance au glucose oral ont été inclus dans cette étude. Ils ont été classés selon les groupes suivants: tolérance normale au glucose (NGT, n=42), altération de la glycémie à jeun (IFG, n=36), intolérance au glucose (IGT, n=92, y compris 44patients IGT1et 48patients IGT2) et IFG+IGT (n=40). Taux d’APN, d’apeline et d’ADMA, pression artérielle, lipides sanguins, insuline, indice de masse corporelle (IMC), et évaluation de modèle d’homéostasie de la résistance à l’insuline (HOMA-IR) ont été notés. La gravité et l’étendue de l’athérosclérose coronarienne ont été déterminées par le score Gensini.

    La prévalence de la maladie coronarienne et les scores Gensini étaient similaires dans les groupes IGT et IFG+IGT mais étaient tous deux plus élevés dans les groupes NGT et IFG (p<0,05). Un taux abaissé d’apeline et élévé d’ADMA étaient relevés dans les groupes IGT et IGT+IFG comparé aux groupes NGT et IFG (p<0,05). Le groupe IGT2avait des taux de 2heures PG et d’apeline ainsi qu’un score Gensini supérieurs mais un taux d’APN inféreur au groupe IGT1 (p<0,05). Le score Gensini était positivement corrélé avec l’apeline (r=0,669) et l’ADMA (r=0,764), mais négativement avec l’apodinectine (r=–0,555, p<0,001). L’ADMA et l’APN étaient les facteurs indépendants affectant le score Gensini.

    Les taux d’ADMA et d’APN pourraient être des facteurs prédictifs de macroangiopathie chez les patients IGR, en particulier dans les cas d’intolérance au glucose.

  • Research article

    Comparison Between CKD-EPI Creatinine and MDRD Equations to Estimate Glomerular Filtration Rate in Kidney Transplant Patients

    Transplantation Proceedings, Volume 48, Issue 2, 2016, pp. 625-630

    (Video) Metabolism of METHOTREXATE - medical animation

    The Modification of Diet in Renal Disease (MDRD) equation is widely used to estimate glomerular filtration rate (eGFR) in kidney transplant (KT) patients. The novel Chronic Kidney Disease–Epidemiology Collaboration equation (CKD-EPI) could improve accuracy of GFR estimation. Our aim was to compare both equations for staging of CKD in KT patients.

    In a cohort of KT patients, correlation of eGFR according to MDRD and CKD-EPI with 24-hour creatinine clearance (24h-CrCl) was evaluated. Concordance between both equations for CKD staging was performed. MDRD was used for initial CKD staging. The mean difference of GFR between 24h-CrCl and each equation was calculated and Bland-Altman analysis applied.

    A cohort of 463KT patients were studied: 67% female, overall average age 46 ± 14 years, 41% living donor, mean time of transplantation 71 months (3–95), and mean serum creatinine 1.68 ± 1.03mg/dL. For the whole cohort (all CKD stages), eGFR by CKD-EPI was 5.33mL/min/1.73m2 higher than by MDRD (P< .01). For CKD stages 1, 2, and 3A, the mean eGFR differences (CKD-EPI− MDRD) were 13.98 ± 3.27, 8.2 ± 1.98, and 5.34 ± 1.32mL/min/1,73 m2, respectively. The percentage of patients with eGFR<60mL/min/1.73m2 decreased from 63.8% according to MDRD to 53.9% with the use of CKD-EPI. In women and patients≤65 years old, eGFR by CKD-EPI was 5.98 and 5.81mL/min/1.73m2 higher, respectively, than by MDRD (P< .01).

    The novel CKD-EPI reduces the number of patients with eGFR<60mL/min/1.73m2 and consequently assigns lower CKD stages to our KT population.

  • Research article

    Prediction of nanoparticle prodrug metabolism by pharmacokinetic modeling of biliary excretion

    Journal of Controlled Release, Volume 172, Issue 2, 2013, pp. 558-567

    Pharmacokinetic modeling and simulation is a powerful tool for the prediction of drug concentrations in the absence of analytical techniques that allow for direct quantification. The present study applied this modeling approach to determine active drug release from a nanoparticle prodrug formulation. A comparative pharmacokinetic study of a nanoscale micellar docetaxel (DTX) prodrug, Procet 8, and commercial DTX formulation, Taxotere, was conducted in bile duct cannulated rats. The nanoscale (~40nm) size of the Procet 8 formulation resulted in confinement within the plasma space and high prodrug plasma concentrations. Ex vivo prodrug hydrolysis during plasma sample preparation resulted in unacceptable error that precluded direct measurement of DTX concentrations. Pharmacokinetic modeling of Taxotere and Procet 8 plasma concentrations, and their associated biliary metabolites, allowed for prediction of the DTX concentration profile and DTX bioavailability, and thereby evaluation of Procet 8 metabolism.

    Procet 8 plasma decay and in vitro plasma hydrolytic rates were identical, suggesting that systemic clearance of the prodrug was primarily metabolic. The Procet 8 and Taxotere plasma profiles, and associated docetaxel hydroxy-tert-butyl carbamate (HDTX) metabolite biliary excretion, were best fit by a two compartment model, with both linear and non-linear DTX clearance, and first order Procet 8 hydrolysis. The model estimated HDTX clearance rate agreed with in vitro literature values, supporting the predictability of the proposed model. Model simulation at the 10mg DTX equivalent/kg dose level predicted DTX formation rate-limited kinetics and a peak plasma DTX concentration of 39ng/mL at 4h for Procet 8, in comparison to 2826ng/mL for Taxotere. As a result of nonlinear DTX clearance, the DTX AUCinf for the Procet 8 formulation was predicted to be 2.6 times lower than Taxotere (775 vs. 2017h×ng/mL, respectively), resulting in an absolute bioavailability estimate of 38%. As DTX clearance in man is considered linear, this low bioavailability is likely species-dependent. These data support the use of pharmacokinetic modeling and simulation in cases of complex formulations, where analytical methods for direct measurement of free (released) drug concentrations are unavailable. Uses of such models may include interpretation of preclinical toxicology studies, selection of first in man dosing regimens, and PK/PD model development.

  • Research article

    Statins modulate feedback regulation mechanisms between advanced glycation end-products and C-reactive protein: Evidence in patients with acute myocardial infarction

    European Journal of Pharmaceutical Sciences, Volume 49, Issue 4, 2013, pp. 512-518

    High sensitivity C-reactive protein (hsCRP) and advanced glycation end-products (AGEs) have been proposed as mediators in inflammation and atherosclerosis. Therefore, we studied the relation between AGE and hsCRP in patients with acute myocardial infarction (AMI).

    Patients with AMI diagnosis and satisfying our inclusion criteria were included during 2009–2011 in an unicentre registry of AMI patients for a cross-sectional study. The final cohort was composed of 156 patients (46.2% STEMI and 27.6% with type-2 diabetes). AGE and hsCRP were measured in plasma.

    Diabetic patients were older than non-diabetics (68.6±10.6 vs. 60.4±13.9years; p<0.05), presented more incidence of hypertension (62.8 vs. 36.3%; p<0.05) and were in a higher Killip class (p<0.05). The mean values of fluorescent AGE and hsCRP levels were 61.3±49.8 AU and 2.4±4.0mg/L, respectively, and there were no differences in these parameters between diabetic and non-diabetic patients. A direct association between AGE and hsCRP levels was observed, mainly in diabetic patients (r=0.258; p=0.018). Importantly, this association disappeared in patients who had been treated with statins before their AMI (r=−0.055; p=0.845), but it was maintained in non-diabetic patients naïve for statins treatment (r=0.634; p<0.001), independently of other treatments and confounding parameters.

    This is the first evidence in humans of a feedback regulation mechanism between CRP and the AGE–RAGE axis modulated by statins.

    (Video) Methotrexate - Mechanism of Action
  • Research article

    Clinical and urodynamic outcomes in children with anorectal malformation subtype of recto-bladder neck fistula

    Journal of Pediatric Urology, Volume 13, Issue 4, 2017, pp. 376.e1-376.e6

    Patients with anorectal malformations (ARMs) have a high incidence of genitourinary anomalies. Those with a recto-bladder neck fistula may represent a high-risk group, but their long-term urologic outcomes are poorly described.

    To evaluate the clinical and urodynamic outcomes in a large cohort of patients with an ARM subtype of recto-bladder neck fistula.

    A retrospective cohort study was performed of patients who had been treated for a recto-bladder neck fistula at the present institution since 2007. The primary outcomes were the ability to achieve urinary continence after 4 years of age, and development of a mildly decreased glomerular filtration rate (GFR) or worse (<89ml/min/1.73m2). Continence was defined as the ability to store urine for 3–4h during the day and 8h overnight without leakage.

    Demographic and clinical data are provided in the Summary Table. The most recent urodynamic findings included the presence of detrusor overactivity in 30 (75%) patients, median leak point pressure of 56.0cmH2O (range, 14–140), median functional cystometric capacity at 40cmH2O of 125.5% age-expected capacity (range, 36–473%), and median maximum cystometric capacity of 131.0% age-expected capacity (range, 44–473%). A mildly decreased GFR or worse developed in 13 (24%) patients. Of the 52 (78%) patients who were followed by pediatric urology at the present institution with a median follow-up of 30.9 months (range, 0.0–86.8), 35 (67%) were at least 4 years of age and could be assessed for continence. Continence was achieved in five (14%) patients voiding spontaneously and 15 (43%) performing CIC. Recurrent urinary tract infections (UTI) (OR 0.70, P=0.006) were an independent predictor of incontinence, while urethral anomalies (OR 1.40, P=0.03) were an independent predictor of chronic kidney disease (CKD) on multiple logistic regression analysis.

    The findings favorably compared with other studies, but were more robust due to the size of the cohort and breadth of urologic evaluation. Limitations included the retrospective design at a single institution. Incomplete clinical data and misclassification of continence may have lead to bias.

    This large cohort of patients with an ARM subtype of recto-bladder neck fistula had a high incidence of genitourinary anomalies. They were rarely able to achieve continence with spontaneous voiding alone and were at risk of developing CKD, both of which were likely multifocal in origin. Long-term urologic follow-up is warranted for patients with a recto-bladder neck fistula.

Copyright © 1965 Published by Elsevier Inc.


1. Methotrexate - A drug with multiple clinical uses
2. Methotrexate - Mechanism of action and Side Effects
(Study Rx)
3. Methotrexate for Rheumatoid Arthritis and Psoriatic Arthritis
(Dr. Diana Girnita - Rheumatologist OnCall )
4. Immunosuppressant Drug's - Methotrexate
(YT Productions)
5. Methotrexate Interaction DEADLY | MUST KNOW !!
(Pharmacist Geek)
6. About Methotrexate - Bob's story
(Arthritis Research Canada)
Top Articles
Latest Posts
Article information

Author: Ms. Lucile Johns

Last Updated: 03/28/2023

Views: 6637

Rating: 4 / 5 (61 voted)

Reviews: 92% of readers found this page helpful

Author information

Name: Ms. Lucile Johns

Birthday: 1999-11-16

Address: Suite 237 56046 Walsh Coves, West Enid, VT 46557

Phone: +59115435987187

Job: Education Supervisor

Hobby: Genealogy, Stone skipping, Skydiving, Nordic skating, Couponing, Coloring, Gardening

Introduction: My name is Ms. Lucile Johns, I am a successful, friendly, friendly, homely, adventurous, handsome, delightful person who loves writing and wants to share my knowledge and understanding with you.