Preliminary Model for Methotrexate Pharmacokinetics

After intravenous injection of 31 mg/kg methotrexate (MTX), its concentrations were determined in plasma, liver, kidney, bone marrow, stomach, duodenum, jejunum, colon and muscle up to 23 days, using an enzymatic assay. Plasma pharmacokinetics were described by a triexponential function, with a terminal half-life of 4.2 h. Up to 1.5 h after injection, the initial rapid decline of MTX concentrations in bone marrow, kidney, and liver roughly paralleled that in plasma. The terminal half-life of MTX in bone marrow was greatly prolonged (37 h), while MTX remained nearly constant in liver (0.57 µg/ml) and kidney (0.53 µg/ml) from 6 h to 23 days. In the intestines, luminal as well as tissue MTX concentrations were determined. The stomach showed a triexponential decay of tissue MTX and low luminal concentrations throughout. In the duodenum, the middle of jejunum, and the colon tissue MTX seemed to follow a bi- or triexponential function. However, high luminal concentrations due to MTX biliary excretion, when reaching a given intestinal portion, increased the MTX tissue concentration in this segment.

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“…In laboratory animals, pharmacokinetics of M T X were studied using ' H -M T X [Bischoff et al" 1970[Bischoff et al" . 1971Dedrick et al.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Organ Distribution of Methotrexate in the Rat

Scheufler¹,

Zetler²,

Iven³

1981

Pharmacology

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“…2 (20,21). In man, pharmacokinetics for conventional and high-dose therapy have been investigated, and significant correlations have been established between delayed disappearance of drug from plasma and cerebrospinal fluid, and clinical toxicity (4-6, 22, 23).…”

mentioning

confidence: 99%

Competitive protein binding assay for methotrexate.

Myers¹,

Lippman²,

Elliot³

et al. 1975

Proc. Natl. Acad. Sci. U.S.A.

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(1) and osteogenic sarcoma (2). Both systemic and intrathecal regimens have been hampered by the occasional development of serious toxicities, such as neurologic sequelae (3), renal failure (4), and myelosuppression. While the etiology of these complications is not well understood, they appear in some cases to be associated with delayed elimination of drug from cerebrospinal fluid (5) or the systemic circulation (6), and pharmacokinetic monitoring may be helpful in their prevention and management (6).Heretofore, routine monitoring of methotrexate pharmacokinetics has not been possible in most institutions due to the complexity of existing assay methods. In the present report, we describe the development of a highly specific, rapid, and sensitive assay based on the high affinity binding of methotrexate to dihydrofolate reductase. In addition to its advantages for routine clinical use, the assay has broad potential application to antifolate research in that it utilizes techniques which allow direct measurement of the association constant of antifolates and dihydrofolate reductase under optimum binding conditions. MATERIALS AND METHODSPartially purified dihydrofolate reductase from dichloromethotrexate-resistant Lactobacillus casei (New England Enzyme Center, Boston, Mass.) was used throughout this study. This enzyme preparation formed 4.6 Aumol of tetrahydrofolate/min per mg protein at pH 7.5 and 370 and was able to bind 1.9 nmol of methotrexate per mg of protein at pH 6.2 and 23'.Unlabeled methotrexate (0.15 M potassium phosphate buffer, pH 6.2, and 23°) (Drug Research and Development Branch, National Cancer Institute) and 4-amino-4-deoxy-10-methylpteroic acid (a gift of Dr. David Johns, National Cancer Institute) were purified by chromatography on DEAE-cellulose with a HC03-elution gradient as previously described (7,8). [3',5',9(n)-3H]methotrexate, 9.5 Ci/ mmol (Amersham-Searle) was diluted in 0.1 M potassium phosphate, pH 8.0, to a final concentration of 2 mCi/ml, and stored at -70°. This methotrexate preparation proved unstable and decomposed, forming radioactive decomposition products which were not adsorbable by charcoal, thus increasing the background. For this reason, the labeled methotrexate was also repurified by chromatography on DEAE-cellulose as described above whenever the background exceeded 150 cpm.Plasma samples containing 100 units of heparin per ml were obtained from patients receiving high dose methotrexate infusion and cerebrospinal fluid was obtained from patients receiving intrathecal methotrexate. All samples were stored at -20°. Prior to analysis samples were acidified to Immediately following addition of the enzyme-NADPH solution, the tubes were mixed by Vortex agitation and 25 Al of a charcoal slurry was added (Norit A, 10 g/100 ml; bovine serum albumin, Fraction V, 2.5 g/100 ml; and high-molecular-weight dextran, 0.1 g/100 ml, all from Sigma Chemical Co.) and pH was adjusted to 6.2 with 1 N HCL. Samples were again mixed by Vortex agitation and centrifuged at 700 X g for 30 min. A 200 ...

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“…Extensive work from a typical four-compartment model with flow-limited assumption with or without extensive details for a particular targeted organ to more than ten compartments describing the whole body can be found in the literature (Andersen et al , 1987Bischoff et al 1968Bischoff et al , 1970Bischoff et al , 1975Liu et al 2005;Peters 2008;Peters and Hultin 2008;Ramsey and Andersen 1984;Wang et al 1997). A general consideration of the number of compartments to choose from and the details of the model depend on these information: the target organ, the physicochemical and pharmacologic properties of the drug that determine the drug transfer in the body, and the PK time scale (Bischoff 1975).…”

Section: Number Of Compartments In a Pbpk Modelmentioning

confidence: 99%

“…In their publication on the general solution of a two-compartment model, Bischoff and Dedrick introduced the concept of the elimination-limited assumption, where the mass transfer is much more rapid than the total elimination rate (Bischoff et al 1970). The importance of introducing the elimination-limited concept is to simplify a PBPK model to a one-compartment model.…”

Section: Elimination Limitedmentioning

confidence: 99%

Introduction to Pharmacometrics and Quantitative Pharmacology with an Emphasis on Physiologically Based Pharmacokinetics

Derendorf

2014

Applied Pharmacometrics

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Preliminary Model for Methotrexate Pharmacokinetics

Cited by 108 publications

References 2 publications

Pharmacokinetics and Organ Distribution of Methotrexate in the Rat

Pharmacokinetics and Organ Distribution of Methotrexate in the Rat

Competitive protein binding assay for methotrexate.

Introduction to Pharmacometrics and Quantitative Pharmacology with an Emphasis on Physiologically Based Pharmacokinetics

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