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Methotrexate

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General Features                  Clinical Study                  Chemical Intervention                 Pharmacological Aspects                 
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PHARMACOLOGICAL ASPECTS

Half-life:
levels in
cells/tissues
/organs
Serum/Plasma
level:
Serum/Plasma
constituents/
protein binding
:
Uptake/
Distribution
:
permeability of methotrexaye through the murine blood-brain barrier can be altered with 2000 rad cranial irradiation given in a single fraction.[1]
following administration, it distributes primarily to the non-fatty tissues of the body.[2]
at doses of 140-350 mg/kg of body weight of methotrexaye given in osteosarcoma patients, the distribution volume was 0.186 +/- 0.062 liter/kg. Peak plasma levels ranged from 540 to 1700 microM.[3]
partial intestinal reabsorption is stated to occur.[4]
Diffusion in tumor:
Pathway:
Biotrans-
formation
Location:
metabolites: 2,4-diamino-N10-methylpteroic acid in humans[3]
enzymes
associated
with
metabolism
Methotrexate undergoes hydroxylation by liver aldehyde oxidase.[2]
Effect on Enzymes
(non-target),
protein levels/
influence on
receptors:
It competitively inhibits dihydrofolate reductase[5]
Transporters
/Carriers:
Transport of Methotrexate across the capillary and cell membranes of the liver, kidney, and skin is rapid.[2]
Route of
Elimination:
Methotrexate is cleared from the body through both biliary and urinary routes.[2]
Excretion
/Clearance:
REFERENCES
1. Griffin TW, Rasey JS, Bleyer WA, The effect of photon irradiation on blood-brain barrier permeability to methotrexate in mice. Cancer. 1977;40(3):1109-11.
http://dx.doi.org/10.1002/1097-0142(197709)40:3<1109::AID-CNCR2820400320>3.0.CO;2-5
2. Morrison PF, Dedrick RL, Lutz RJ, Methotrexate: Pharmacokinetics and Assessment of Toxicity; National Research Council (US) Subcommittee on Pharmacokinetics in Risk Assessment. Drinking Water and Health, Volume 8: Pharmacokinetics in Risk Assessment. Washington (DC): National Academies Press (US); 1987.
https://www.ncbi.nlm.nih.gov/books/NBK218077/
3. Breithaupt H, Küenzlen E, Pharmacokinetics of methotrexate and 7-hydroxymethotrexate following infusions of high-dose methotrexate. Cancer Treat Rep. 1982 ;66(9):1733-41.
https://www.ncbi.nlm.nih.gov/pubmed/6956440
4. Bischoff KB et al, Methotrexate Pharmacokinetics. Journal of Pharmaceutical Sciences 1971;60(8):1128-1133.
http://dx.doi.org/10.1002/jps.2600600803
5. Chapter 19: Nitrogen metabolism: nucleotide metabolism; In: Biochemistry and Molecular Biology, 5th edition, by Papachristodoulou D et al, OUP Oxford, 2014, page no. 219.
https://books.google.co.in/books?id=oPtzBAAAQBAJ&pg=PA291