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G Fabre

Publications and source records attributed to G Fabre.

At least 55 records · Page 3Linked to original sources
PubMed1988

Involvement of the macrolide antibiotic inducible cytochrome P-450 LM3c in the metabolism of midazolam by microsomal fractions prepared from rabbit liver.

This report characterizes the cytochrome P-450 isozyme involved in midazolam metabolism. This study was undertaken into liver microsomal fractions prepared from untreated rabbits or animals treated with drugs known to specifically induce various cytochrome P-450 isozymes such as form LM2 by phenobarbital, LM4 and LM6 by 3-methylcholanthrene and beta-naphthoflavone, LM3a by ethyl alcohol and acetone, and LM3c by macrolide antibiotics (rifampicin, erythromycin and triacetyloleandomycin). Among this library of characterized microsomal preparations, only those obtained from macrolide antibiotic-treated rabbits exhibited a Type I binding spectrum upon addition of midazolam (Ks = 3.2-5.3 micrograms/ml; 10.6-17.5 microM) and significantly metabolized midazolam to its various hydroxylated metabolites (Km = 2.52 +/- 0.22 micrograms/ml; 8.32 +/- 0.73 microM and Vmax = 20 micrograms metabolites formed/min/mg proteins; 66 nmoles metabolites formed/min/mg proteins). The following observations further confirmed the specific involvement of the cytochrome P-450 LM3c isozyme: (i) only anti-cytochrome P-450 LM3c isozyme antibodies intensively inhibited midazolam metabolism, (ii) incubation of microsomes, prepared from TAO-treated rabbits, with midazolam in the presence of potassium ferricyanide which restored the functional cytochrome P-450 LM3c isozyme, increased midazolam metabolism to a similar extent, and (iii) in the presence of Cyclosporin A, a specific substrate of the rabbit cytochrome P-450 LM3c isozyme, midazolam metabolism was inhibited in a concentration-dependent manner. These data demonstrated that the rabbit cytochrome P-450 LM3c isozyme was predominantly involved in midazolam metabolism.

Animals↗
PubMed1988

Interactions between 7-hydroxymethotrexate and folinic acid in RAJI cells, in vitro.

HPLC analysis of plasma samples obtained from patients included in a high-dose methotrexate-folinic acid Rescue (HD-MTX-CF) protocol, allowed the simultaneous determination of MTX, CF and their respective plasma metabolites, 7-hydroxymethotrexate (7-OH-MTX) and 5-methyltetrahydrofolate (5-CH3-FH4). These 4 compounds interact at the cellular level to ensure the selective effectiveness of the HD-MTX-CF rescue protocol. An in vitro study has been investigated in RAJI cells to better describe the interference of CF on uptake, accumulation and metabolism of [3H]7-OH-MTX. Results about uptake and accumulation of CF were also obtained using [3H]CF, in the absence or the presence of unlabeled 7-OH-MTX. The rate of [3H]7-OH-MTX influx in RAJI cells (Km = 25.30 +/- 7.75 microM, n = 3) was competitively inhibited by the presence of 10 microM CF with a Ki value of 6.00 +/- 1.94 microM (n = 2). Intracellular 7-OH-MTX accumulation was decreased by approximately 30% when extracellular CF concentration was twice as high as that of 7-OH-MTX, and 70% when CF extracellular concentration was 5 times higher. The metabolism of 7-OH-MTX to its intracellular polyglutamyl derivatives was depressed by 90% when 10 microM CF were incubated for 2 h with equimolar [3H]7-OH-MTX, and it was completely abolished in the presence of 100 microM CF.

Animals↗
PubMed1988

[Comparison of thawing of plasma by microwave or water bath: preliminary longitudinal biological study of hemostatic parameters].

Exploration of haemostasis was performed on plasmas thawed in an experimental microwave oven comparatively to a 37 degrees C water bath. Factor VIII:R:Ag, procoagulant and antigenic fibrinogen, and Fg:C/Fg:Ag ratio were found to be significantly, slightly decreased with microwave thawing. Factor VIII:C and VIII:C/VIII:R:Ag ratio were found to be increased with microwaves. Antigenic fractions were decreased because of partial precipitation. In addition, Fibrinogen slightly lost its activity; on the contrary, factor VIIIC was activated by micro-waves. All this allows to select parameters for new experimental microwave ovens development.

Blood Coagulation Factors↗
PubMed1988

Extrapolation of preclinical pharmacokinetic data to therapeutic drug use.

1. Preclinical in vivo and in vitro studies are fundamental to the safe and effective development of new drugs. 2. Pharmacokinetic and metabolic research is essential to a better understanding of the pharmacological and toxicological activities of drugs and their metabolites. 3. Data generated by such a strategy can be used to improve Phase I trials, particularly those for anticancer drugs. 4. Human and animal in vitro models are potentially powerful preclinical tools in: (i) The prediction of the pharmacological behaviour of analogues belonging to the same family, e.g. vinca alkaloids; (ii) The selection of the animal species most closely related to humans on the basis of metabolic pattern; (iii) The assessment of the duration of drug action--particularly those drugs exhibiting different metabolic clearances (e.g. benzodiazepines); (iv) The understanding and prediction of drug interactions, i.e. those described for cyclosporin A and macrolide antibiotics; and (v) The explanation of the metabolic origins of interindividual variabilities in pharmacological activity.

Animals↗
PubMed1987

Prevalence of hepatitis A antibodies in French recruits in 1985.

The epidemiological study of hepatitis A antibodies prevalence in 1000 french recruits shows a 20% fall in people of 18-20 years old between 1979 and 1985, and identifies variables such as residence in coasting area, stay overseas, study level, as the most important social and geographical risk factors. These results are in agreement with the evolution observed in different other european countries.

Adolescent↗
PubMed1987

Plasma kinetic study of folinic acid and 5-methyltetrahydrofolate in healthy volunteers and cancer patients by high-performance liquid chromatography.

A reversed-phase HPLC method is described for the simultaneous determination of folinic acid, MTX, and their plasma metabolites 5-CH3-FH4 and 7-OH-MTX respectively. In addition, this technique allows the separation of FA another naturally occurring folate, and of AMT, used as internal standard. Separation of these compounds was achieved on a Waters Spherical C18 column at a flow rate of 0.8 ml.min-1. Elution was carried out with 0.1 M sodium acetate buffer (pH 5.5) as solvent A and 7.5% acetonitrile 92.5% bidistilled water as solvent B. UV detection was performed at 280 nm. This method was applied in a pharmacokinetic study of folinic acid and its plasma metabolite 5-CH3-FH4 following two different protocols: (1) i.v. bolus injection of 50 mg calcium folinate in six healthy volunteers and (2) simultaneous i.v. bolus injections of 50 mg/m2 MTX and 50 mg/m2 folinic acid in four cancer patients. Mean apparent half-life values for folinic acid and its metabolite were 7.02 +/- 1.81 h and 3.90 +/- 0.86 respectively in the first protocol, 4.80 +/- 1.48 h and 4.74 +/- 1.47 h in the second protocol. MTX and 7-OH-MTX were also quantified in the second protocol and were found not to affect the pharmacokinetics of folinic acid and 5-CH3-FH4. Since in vitro studies on metabolism of folinic acid might be of great interest in trying to assess the mechanism of action of the folates and the potential interaction of MTX and 7-OH-MTX in this mechanism via the metabolism, the chromatographic method we describe here has been adapted for the separation of all the potential intracellular monoglutamyl metabolites of folinic acid.

Adult↗
PubMed1986

Kinetics of uptake and intracellular binding of Cyclosporine A in RAJI cells, in vitro.

Uptake characteristics of Cyclosporine A (CsA), an immunosuppressive agent widely used in organ transplantation, have been evaluated in RAJI cells, a human Burkitt lymphoma cell line which (i) does not bear T-cell markers, (ii) is insensitive to CsA after a 1 hr exposure to concentrations up to 50 micrograms/ml, and (iii) does not metabolize CsA. CsA is rapidly accumulated inside the cells until a near steady-state is achieved (within 1-3 min). This uptake is characterized by two components: one linear process saturable at low drug concentrations (lower than 1 microgram/ml) and another not saturable component even at high drug concentrations (up to 50 micrograms/ml). Uptake of CsA is temperature-dependent and unaffected by the presence of CsD, a structural CsA analog (50 micrograms/ml CsD) or sodium azide (10 mM) in the extracellular compartment. Intracellular accumulation of CsA is associated with the rapid appearance of a cytosolic drug-protein complex, which is responsible at least in part, for the large amount of total drug accumulated inside the cells. Chromatographic analysis of this (3H)CsA-macromolecule complex on a Bio-Gel P-60 exclusion column demonstrates that the molecular weight of this protein(s), likely cyclophilin, is around 15,000-20,000 daltons. Using Lineweaver-Burk analysis of binding equilibrium data, the dissociation constant of CsA for this binding site was approximately 2.2 microM. these studies, which demonstrate that CsA (i) is rapidly accumulated inside the cells as free drug but is also specifically bound to an intracellular macromolecule, and (ii) is selectively retained in the intracellular compartment after the extracellular drug is removed, could explain the intense distribution of CsA in the organs and the slow disappearance of CsA from plasma after CsA therapy in humans.

Burkitt Lymphoma↗
PubMed1986

Hydroxylation of 4-amino-antifolates by partially purified aldehyde oxidase from rabbit liver.

This paper explores the interaction between 4-amino-antifolates and aldehyde oxidase (aldehyde: O2 oxidoreductase, EC 1.2.3.1) that was purified 60- to 120-fold from rabbit liver with yields of 5-15%. The purification procedure consisted of one heat and two ammonium sulfate precipitations followed by chromatography on hydroxylapatite and then Sephacryl S-200. Analysis of initial rates of hydroxylation of methotrexate, aminopterin and dichloromethotrexate indicated an order of affinities of dichloromethotrexate (10 microM) greater than methotrexate (35 microM) greater than aminopterin (272 microM). There was no difference in the Vmax of methotrexate and dichloromethotrexate (248 and 231 nmoles/min/mg protein respectively); aminopterin (130 nmoles/min/mg protein) was less than that of the other two. The Vmax/Km ratios were 24.1, 7.20 and 0.48 for dichloromethotrexate, methotrexate and aminopterin respectively. This enzyme preparation also mediated the hydroxylation of methotrexate polyglutamyl derivatives with a decrease in the rates of hydroxylation, as the total number of glutamyl residues was increased to four, a consequence of a marked increase in Km values and/or decrease in Vmax; the ratios of the Vmax/Km for the di-, tri-, and tetraglutamates were 0.94, 0.31 and 0.21 respectively. This low activity of the polyglutamyl derivatives of methotrexate for aldehyde oxidase is consistent with the observations that the predominant forms of 4-amino-antifolate polyglutamates found in human liver after administration of methotrexate are the polyglutamyl derivatives of the parent compound. Finally, substrate inhibition for methotrexate and dichloromethotrexate was observed at concentrations in excess of 150 and 30 microM, respectively, about 5- and 3-fold higher than their respective Km values. Hence, while dichloromethotrexate had the lowest Km for aldehyde oxidase amongst the 4-amino-antifolates studied, the actual rates of hydroxylation depended upon the concentration employed because of substrate inhibition. Aminopterin was a very poor substrate for this enzyme at low and saturating concentrations. These properties of the hydroxylation of 4-amino-antifolates may be of importance in the design of clinical regimens with these agents--in particular, regimens that employ infusion of these drugs into the hepatic artery. However, the relevance of these observations to the hydroxylation of 4-amino-antifolates by human liver remains to be established.

Aldehyde Oxidase↗
PubMed1986

7-Hydroxymethotrexate cytotoxicity and selectivity in a human Burkitt's lymphoma cell line versus human granulocytic progenitor cells: rescue by folinic acid and nucleosides.

The cytotoxicity of 7-hydroxymethotrexate (7-OH-MTX), the primary plasma metabolite of methotrexate (MTX) in humans, was assessed by inhibition of colony formation in agar, using human bone marrow granulocyte-macrophage stem cells (CFU) from healthy volunteers and RAJI cells, a human Burkitt's lymphoma cell line. After a 2 hr exposure of cells to 7-OH-MTX, the concentrations necessary to produce a 50% inhibition of colony formation were 180 microM and 10 microM for bone marrow cells and for RAJI cells respectively. A continuous incubation with 20 microM folinic acid (CF) protected the RAJI cells from 7-OH-MTX cytotoxicity at concentrations below 5 microM but was not able to completely reverse 7-OH-MTX effects at higher doses. Continuous incubation of 7-OH-MTX-preloaded cells (2 hr, ID90) with the end products of folate-dependent reactions, adenosine (100 microM) and thymidine (10 microM), completely rescued RAJI cells from the 7-OH-MTX cytotoxic effects. Moreover, while thymidine alone had no effect on the 7-OH-MTX response curve, both adenosine alone or CF-adenosine combination produced 75% and 90% protection respectively. CF and adenosine concentrations necessary to achieve 90% protection were 20 and 100 microM respectively. This study demonstrates that 7-OH-MTX can exhibit a cytotoxic selectivity for this human Burkitt's lymphoma cell line as compared to human bone marrow stem cells and the cytotoxicity of 7-OH-MTX cannot be reversed by CF alone. These data suggest that 7-OH-MTX and/or its polyglutamylated derivatives may play an important role on different enzyme(s) involved in the interconversion of tetrahydrofolate cofactors necessary for the de novo purine biosynthesis.

Burkitt Lymphoma↗
PubMed1985

[Platelet preservation in a new type of plastic material. Functional in vitro study].

We report the comparison of the fonctionnal platelet criteria's evolution studied in vitro by aggregation with different agents, by osmotic stress, ATP total amount and platelet volume distribution for six days of storage in two different PVC bags. The results indicate that: platelet's evolution appears more appreciable when tested by aggregation with an important amount of collagen, by hypotonic stress and volume distribution. The difference between the two different bags is shown as early as the thirs day of storage; for quality control, we can choose some criteria despite the absence of their clear correlation with transfusion efficiency.

Adenosine Triphosphate↗
PubMed1985

Formation of 7-hydroxymethotrexate polyglutamyl derivatives and their cytotoxicity in human chronic myelogenous leukemia cells, in vitro.

The rapid synthesis of poly-gamma-glutamyl derivatives of 7-hydroxymethotrexate (7-OH-MTX) and their selective intracellular retention are reported in human chronic myelogenous leukemia cells, K-562. After a 30-min exposure to 5 microM [3H]7-OH-MTX, three different polyglutamyl derivatives were detected by high-performance liquid chromatography. When extracellular 7-OH-MTX was removed, the 7-OH-MTX diglutamate level declined slowly in comparison to the monoglutamate, but the higher polyglutamyl derivative levels increased. Within 10 min after exposure of cells to 7-OH-MTX, the level of these polyglutamyl derivatives far exceeds the dihydrofolate reductase binding capacity. Gel filtration or charcoal binding analysis followed by high-performance liquid chromatography analysis of the bound component showed intracellular binding of virtually all 7-OH-MTX tetraglutamate at a level 4-fold higher than that of the dihydrofolate reductase binding capacity. No bound 7-OH-MTX diglutamate or triglutamate could be detected. Treatment of the 7-OH-MTX tetraglutamate: protein complex with 100 microM unlabeled methotrexate (MTX) for 15 min resulted in only a partial dissociation of this complex to an extent compatible with the dihydrofolate reductase level. The residual 7-OH-MTX tetraglutamate remained bound to a site with a molecular weight of approximately 25,000 to 35,000 as assessed by Bio-Gel P-60 analysis and could not be displaced by folic acid, 5-formyltetrahydrofolate, 7-OH-MTX, or the tetraglutamate of MTX. 7-OH-MTX and MTX cytotoxicities were compared by clonogenic assay in agar and by their effects on cell growth. After a 2-hr exposure, the 50% inhibitory concentrations for 7-OH-MTX and MTX in cells growing in agar were 10(-5) and 10(-6) M, respectively. A 10-fold difference in cytotoxicity was also observed in cells growing in suspension. Continuous exposure to glycine: adenosine: thymidine completely protects cells from a sustained exposure to 7-OH-MTX over the entire period of clonal growth. However, even a brief exposure to 7-OH-MTX also requires continuous exposure to glycine: adenosine: thymidine for protection. This suggests that, as observed for MTX, the 7-OH-MTX polyglutamyl derivatives that are retained within the cells have a sustained cytotoxic effect after the monoglutamate is removed.

Cell Division↗
PubMed1985

Characteristics of the formation and membrane transport of 7-hydroxymethotrexate in freshly isolated rabbit hepatocytes.

The cellular pharmacology of methotrexate was evaluated in freshly isolated rabbit hepatocytes in suspension with an analysis of drug metabolism by high-performance liquid chromatography. After exposure of hepatocytes at a cytocrit of 5% to 5 microM [3H]-methotrexate, intracellular 7-hydroxymethotrexate appears rapidly within the cell; within 15 sec, the level of 7-hydroxymethotrexate exceeds the level of intracellular methotrexate, although the latter has not achieved the dihydrofolate reductase binding capacity. Within 20 min, virtually all methotrexate is hydroxylated. There is minimal formation of methotrexate polyglutamyl derivatives even after exposure of cells to very high levels of methotrexate, and 7-hydroxymethotrexate polyglutamates do not accumulate in the cell at all after incubation with [3H]-7-hydroxymethotrexate. Because of the rapidity of the hydroxylation of methotrexate, transport of this agent could not be characterized. However, some aspects of the transport properties of 7-hydroxymethotrexate could be studied since the catabolite is neither bound nor metabolized in this system. Net 7-hydroxymethotrexate transport was reduced by the addition of 5-formyltetrahydrofolate. As observed for 4-aminoantifolate transport in other cell systems, net 7-hydroxymethotrexate transport was markedly stimulated by sodium azide, an inhibitor of energy metabolism. The data suggest that hydroxylation of methotrexate proceeds at a rate at least comparable to the rate of association of the drug with dihydrofolate reductase and that transport of methotrexate into rabbit hepatocytes is slow relative to the rate of catabolism to the 7-hydroxy derivative. Rabbit hepatocytes may be a useful model for exploring methotrexate catabolism at the cellular level and may provide insights into the interaction between methotrexate and/or other 4-aminoantifolates and the human liver.

Animals↗
PubMed1984

Synthesis and properties of 7-hydroxymethotrexate polyglutamyl derivatives in Ehrlich ascites tumor cells in vitro.

The synthesis of poly-gamma-glutamyl derivatives of 7-hydroxymethotrexate (7-OH-4-NH2-10-CH3-pteroyl-glutamic acid (PteGlu1] was evaluated by direct hydroxylation of the tetraglutamyl derivative of methotrexate (4-NH2-10-CH3-PteGlu4) by a cell-free preparation of rabbit liver aldehyde oxidase and by polyglutamylation of 7-OH-methotrexate in Ehrlich ascites tumor cells in vitro. The polyglutamyl derivatives of 7-OH-methotrexate rapidly accumulate in cells to the 7-OH-4-NH2-10-CH3-PteGlu4. While 7-OH-methotrexate monoglutamate does not bind to dihydrofolate reductase, 7-OH-4-NH2-10-CH3-PteGlu4 does bind to the enzyme as established by gel filtration analysis of cell extracts and by use of purified dihydrofolate reductase from Ehrlich cells. Within cells, the rate of formation of 7-OH-methotrexate polyglutamyl derivatives exceeds that for methotrexate by a factor of 2.7 at comparable free monoglutamyl substrate levels, suggesting that 7-OH-methotrexate may be a better substrate than methotrexate for the folylpolyglutamate synthetase. 7-OH-methotrexate slows the rate of methotrexate polyglutamylation in cells, a consequence of the inhibition of methotrexate transport with reduced methotrexate substrate available for polyglutamylation. When 7-OH-methotrexate polyglutamyl derivatives were accumulated inside the cells following which extracellular 7-OH-methotrexate was removed, the monoglutamate, and to a lesser extent the diglutamate, exited the cells whereas the majority of the longer polyglutamyl derivatives were retained and continued to be metabolized to higher forms. These studies suggest that 7-OH-methotrexate and its polyglutamyl derivatives may play a role in modulating methotrexate action, either by their own inhibitory effects on folate-dependent enzymes or by their effects on methotrexate transport and metabolism within cells.

Aldehyde Oxidase↗
PubMed1984

Assay of methotrexate and 7-hydroxymethotrexate by gradient-elution high-performance liquid chromatography and its application in a high-dose pharmacokinetic study.

A paired-ion high-performance liquid chromatographic method is described for the simultaneous determination of methotrexate (MTX) and its major metabolise, 7-hydroxymethotrexate (7-OH-MTX), in plasma and urine. In addition, this technique permits the separation of other known metabolites of MTX, such as DAMPA and MTX-polyglutamates. After selective extraction on an anion-exchange resin column, both compounds and the internal standard, aminopterin, were separated on a reversed-phase octadecylsilane column with UV-detection at 313 nm. The detection limits for plasma and urine samples were approximately 40 ng/ml (8.8 x 10(-8) M) for MTX and 100 ng/ml (2.1 x 10(-7) M) for 7-OH-MTX. This method was applied in pharmacokinetic studies following 24-h infusion of high-dose MTX in four patients during two successive treatments. After the end of the infusion, the mean apparent half-life for the metabolite was 19.1 h, while that for MTX was 8.8 h. A stepwise increase in the plasma concentrations of both MTX and its metabolite was observed during the second MTX infusion. This increase was reflected in the cumulative urinary excretion of both drug and its metabolite.

Journal Article↗
PubMed1984

Polyglutamylation, an important element in methotrexate cytotoxicity and selectivity in tumor versus murine granulocytic progenitor cells in vitro.

Methotrexate (MTX) cytotoxicity was assessed by clonogenic assay in agar with granulocytic progenitor cells from mouse bone marrow and in the Ehrlich ascites tumor, the K562 human chronic myelogenous leukemia, and the P388 murine leukemia. After a 2-hr exposure to MTX, the concentrations necessary to produce 50% inhibition of colony formation were 100, 25, 1.2, and 0.25 microM, respectively. This was inversely related to the ability of the tumor cells to accumulate MTX polyglutamyl derivatives and consistent with the observation that no polyglutamyl derivatives were observed in granulocytic progenitor cells after a 2-hr exposure to 5 micron MTX. Continuous exposure to glycine (200 microM)-adenosine (100 microM)-thymidine (10 microM) (GAT), along with MTX, protected cells from MTX cytotoxicity by circumventing the requirement for tetrahydrofolate cofactors. However, while the presence of GAT during a 2-hr exposure to 5 microM MTX is sufficient to protect granulocyte progenitor cells from MTX cytotoxicity, the presence of GAT, even after MTX is removed, is required to protect tumor cells. Indeed, if, after a 2-hr exposure of tumor cells to MTX and GAT, both MTX and GAT are removed before plating in agar, cytotoxicity to tumor cells was expressed. This sustained antitumor effect of MTX correlates with the rapid build-up of polyglutamyl derivatives that are retained in the cell even after extracellular and intracellular monoglutamate is eliminated. This is in contrast to granulocytic progenitor cells which appear to be susceptible to the drug only during the period of exposure to the monoglutamate under these conditions. The data strongly suggest that the marked differences in the accumulation of MTX polyglutamyl derivatives between the tumor cells studied and the murine bone marrow granulocytic progenitor cells are an important element in MTX selectivity.

Animals↗
PubMed1984

Interactions between 7-hydroxymethotrexate and methotrexate at the cellular level in the Ehrlich ascites tumor in vitro.

Studies were undertaken to characterize the cellular pharmacology of 7-hydroxymethotrexate (7-OH-MTX) in Ehrlich ascites tumor cells, compare it to that of methotrexate (MTX), and define the interactions between the parent compound and its catabolite. Transport of 7-OH-MTX is mediated by the MTX-tetrahydrofolate cofactor carrier, with a Km of 9 microM in comparison to the MTX Km of 5 microM. Both compounds mutually inhibit their influx and steady-state levels of free drug accumulated. While influx of 7-OH-MTX is slower than influx of MTX, 7-OH-MTX efflux is likewise slower, so that the steady-state level of 7-OH-MTX achieved is comparable to that of MTX. Influx of 7-OH-MTX is inhibited by extracellular 5-formyltetrahydrofolate and trans-stimulated in cells preloaded with this tetrahydrofolate cofactor. The energetics of 7-OH-MTX transport is similar to that of MTX in the influx and net transport are stimulated by sodium azide, while net transport is reduced by glucose. As observed for MTX, 7-OH-MTX transport is sensitive to the anionic composition of the extracellular compartment and was shown to be inhibited by organic and inorganic phosphates. 7-OH-MTX does not, alone, inhibit [3H]deoxyuridine incorporation into DNA at concentrations of up to 50 microM. However, the catabolite reduces MTX inhibition of deoxyuridine metabolism, presumably due to the reduction in the free level of intracellular MTX achieved. These findings support the possibility that when 7-OH-MTX accumulates to high levels relative to MTX in clinical regimens, it may modulate the pharmacological effects of MTX.

Animals↗