Pharmacokinetics and Organ Distribution of Methotrexate in the Rat

Scheufler, E; Zetler, G.; Iven, H.

doi:10.1159/000137531

Cited by 15 publications

(4 citation statements)

References 5 publications

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“…MTX concentrations were relatively low in the lung, spleen and marrow (Fig. 3), and the concentration of MTX in the heart was too low to test, which is roughly consistent with previous studies (37,38). When co-administered with SGR, the concentration of MTX in tissues changed in a tissue-and time-dependent manner.…”

Section: Genesupporting

confidence: 89%

Smilax glabra Rhizoma affects the pharmacokinetics and tissue distribution of methotrexate by increasing the P-glycoprotein mRNA expression in rats after oral administration

Shigui

Zhao

et al. 2017

Molecular Medicine Reports

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Methotrexate (MTX) is a widely used immunosuppressant and anticancer agent with high toxicity. Smilax glabra Rhizoma (SGR) has the effect of detoxification and immunoregulation, and has been used as both food and folk medicine in many countries. Co‑administration of MTX and SGR occurs in several diseases. However, whether they work synergistically or are incompatible remains unknown. In the present study, MTX was administrated to rats alone or combined with SGR. Blood and tissue samples were collected at designated times. The concentrations of MTX were determined by high‑performance liquid chromatography. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was used to detected the gene expression. SGR decreased the AUC0‑t and Cmax of MTX by 44.5 and 48.2%, but in a tissue‑dependent manner. The total exposure of MTX was significantly decreased in the small intestine, stomach, plasma, and kidney by 61.6, 34.7, 63.3 and 46.1%, respectively, but was increased in the lung and spleen by 82.9 and 21.0%, respectively. RT‑qPCR demonstrated that SGR increased the mean P‑glycoprotein (gp) mRNA expression in the small intestine 2.54 times, but had a marginal effect on the expression of organic anion transporting polypeptide 2, and organic anion transporter (OAT)1 and OAT2. These results suggested that SGR affects the pharmacokinetics of MTX in a tissue‑dependent manner by affecting P‑gp, and the clinical effect of co‑administration depended on the disease site.

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Section: Genesupporting

confidence: 89%

Smilax glabra Rhizoma affects the pharmacokinetics and tissue distribution of methotrexate by increasing the P-glycoprotein mRNA expression in rats after oral administration

Shigui

Zhao

et al. 2017

Molecular Medicine Reports

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“…The animals were killed and samples of plas ma, kidney, liver, and bone marrow were taken for MTX analysis. For further details on sample prepara tion see Scheufler et al [1981], MTX concentrations were measured by an enzymatic assay [Scheufler, 1981]. At 31 mg/kg, 5-6 animals were taken for each sampling time , whereas only 3 animals each were taken for each sampling time after the intravenous administration of the two lower doses.…”

Section: Methodsmentioning

confidence: 99%

Evidence for Nonlinear Pharmacokinetics of Methotrexate in the Rat

Scheufler¹

1982

Pharmacology

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Three doses (0.31, 3.1 and 31 mg/kg) of methotrexate (MTX) were given intravenously to rats. The resulting concentration-time curves in plasma (normalized by dividing the plasma concentration by a multiple of the dose) were not superimposable, indicating nonlinear plasma pharmacokinetics. In liver, kidney, bone marrow and stomach a tissue-specific, very slowly (or not measurably) decreasing terminal plateau phase could be observed after administration of all three doses. This was explained by a strong binding of MTX to dihydrofolate reductase. The ratio, exchangeable MTX in tissue/plasma concentration, increased in liver and kidney with time after the higher doses, which is in accord with saturable transport to tissues.

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“…Prior researchers have used two and three compartment models ,, to fit the pharmacokinetics of methotrexate. The amplitudes of the second and third phase or phases, however, are quite small, and their timescales are quite long.…”

Section: Resultsmentioning

confidence: 99%

“…The amplitudes of the second and third phase or phases, however, are quite small, and their timescales are quite long. Scheufler and co-workers, for example, reported a rapid phase (11 min lifetime) of amplitude 330 μM and two additional slower phases (of lifetimes 37.5 min and 6 h) whose combined amplitudes reach only 70 μM. That is, more than 80% of the total change in concentration is captured in the most rapid of the three phases, which is the phase that dominates our observation period.…”

Section: Resultsmentioning

confidence: 99%

Real-Time, Seconds-Resolved Measurements of Plasma Methotrexate In Situ in the Living Body

et al. 2022

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Dose-limiting toxicity and significant patient-to-patient pharmacokinetic variability often render it difficult to achieve the safe and effective dosing of drugs. This is further compounded by the slow, cumbersome nature of the analytical methods used to monitor patient-specific pharmacokinetics, which inevitably rely on blood draws followed by post-facto laboratory analysis. Motivated by the pressing need for improved “therapeutic drug monitoring”, we are developing electrochemical aptamer-based (EAB) sensors, a minimally invasive biosensor architecture that can provide real-time, seconds-resolved measurements of drug levels in situ in the living body. A key advantage of EAB sensors is that they are generalizable to the detection of a wide range of therapeutic agents because they are independent of the chemical or enzymatic reactivity of their targets. Three of the four therapeutic drug classes that have, to date, been shown measurable using in vivo EAB sensors, however, bind to nucleic acids as part of their mode of action, leaving open questions regarding the extent to which the approach can be generalized to therapeutics that do not. Here, we demonstrate real-time, in vivo measurements of plasma methotrexate, an antimetabolite (a mode of action not reliant on DNA binding) chemotherapeutic, following human-relevant dosing in a live rat animal model. By providing hundreds of drug concentration values, the resulting seconds-resolved measurements succeed in defining key pharmacokinetic parameters, including the drug’s elimination rate, peak plasma concentration, and exposure (area under the curve), with unprecedented 5 to 10% precision. With this level of precision, we easily identify significant (>2-fold) differences in drug exposure occurring between even healthy rats given the same mass-adjusted methotrexate dose. By providing a real-time, seconds-resolved window into methotrexate pharmacokinetics, such measurements can be used to precisely “individualize” the dosing of this significantly toxic yet vitally important chemotherapeutic.

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Pharmacokinetics and Organ Distribution of Methotrexate in the Rat

Cited by 15 publications

References 5 publications

Smilax glabra Rhizoma affects the pharmacokinetics and tissue distribution of methotrexate by increasing the P-glycoprotein mRNA expression in rats after oral administration

Smilax glabra Rhizoma affects the pharmacokinetics and tissue distribution of methotrexate by increasing the P-glycoprotein mRNA expression in rats after oral administration

Evidence for Nonlinear Pharmacokinetics of Methotrexate in the Rat

Real-Time, Seconds-Resolved Measurements of Plasma Methotrexate In Situ in the Living Body

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