Medical Pharmacology Chapter 33-34: Anticancer Drugs
Antifolate Analogues: Methotrexate continued
Absorption, Distribution, Biotransformation, Excretion:1
Methotrexate is absorbed from the G.I. tract readily, although higher doses may be absorbed incompletely.
For higher doses, intravenous administration may be preferable.
At the higher doses, doses exceeding 25 mg/m2 oral bioavailability becomes saturated and may be unreliable.3
.At typical methotrexate doses, CSF levels may be only about 3% compared to that in the systemic circulation at steady-state.
However, at high dose methotrexate, cytotoxic methotrexate levels can be found in the CNS, the drug having crossed the blood-brain barrier.1
Following IV administration, the drug moves from plasma to other compartments, in a triphasic manner.1,11
The initial phase is one of rapid distribution with the second phase indicative of renal clearance showing a t1/2 of about 2-3 hours.
Renal excretion represents the primary route of elimination (glomerular filtration as well as tubular secretion). If the patient exhibits renal dysfunction, dosage modification may be appropriate.3
The last phase, the third phase, exhibits a half-life of about 9 hours.
This final phase, the terminal phase may be extended due to renal failure and may be causative of significant drug toxicity which references bone marrow, skin, and G.I. epithelium.
Methotrexate distribution into body compartments evolve slowly.
Plural or peritoneal sites, if larger than normal due to ascites or pleural effusion, may serve as a significant story site which promotes extended slow drug release with elevation of plasma levels and more prominent bone marrow toxicities.1
Other drugs may inhibit methotrexate renal excretion and predisposed to methotrexate toxicities.
These drugs include aspirin, nonsteroidal anti-inflammatory drugs, probenecid, cephalosporins as well as penicillin.3,8
About half of methotrexate is found bound to plasma proteins, primarily albumin, and may be displaced from these proteins by many drugs.
Examples of drugs that displace bound (inactive while bound) methotrexate from plasma proteins include chloramphenicol, phenytoin, tetracycline, salicylates and sulfonamides.
The expectable steady-state levels of methotrexate may be increased if these drugs are given along with methotrexate.
Given the dependence of methotrexate upon the kidneys for excretion (as much as 90%), drugs that decrease renal blood flow (the nonsteroidal anti-inflammatory drugs do this) can reduce methotrexate excretion which in turn can promote significant myelosupression.
Other mechanisms that reduce renal excretion of methotrexate include the presence of drugs that are inherently nephrotoxic or that are classified as weak organic acids
Genetic changes can also influence cellular responses to antifolates as well as change baseline toxicities.1
For example, a substitution (C677T) in methylenetetrahydrofolate reductase decreases enzyme activity involved in catalyzing N5-10 methylene FH4, the thymidylate synthase cofactor.
As a consequence, methotrexate toxicity is enhanced.
This particular pharmacogenetic effect, a leukemic cell polymorphism, would be associated with increased methotrexate sensitivity.
Also, toxicity and therapeutic effects of another antifolate analog, pemetrexed (an important thymidylate synthase inhibitor) might also be influenced.1
Another polymorphism, this time associated with the thymidylate synthase promoter region would alter the enzyme's expression.
The resultant change in intracellular thymidylate synthase concentrations would be expected to alter response as well as toxicity of both antifolates and fluoropyrimidines.1
Toxicities and Adverse Effects:8,1
The primary methotrexate side effects our gastrointestinal (G.I.) toxicities and myelosupression.8
Patients receiving methotrexate may also experience spontaneous hemorrhage or serious, life-threatening infection.
In some circumstances platelet transfusions may be appropriate prophylactically as would be administration of broad-spectrum antibiotics.1
The side effects are usually reversible within 2 weeks, assuming drug-elimination systems are intact.8
However, in patients with renal dysfunction, small methotrexate doses can lead to significant toxicities.8
These toxicities result from the substantial dependence on the kidneys for drug excretion.
Intratubular methotrexate precipitation and precipitation of its metabolites in acidic urine can lead to MTX-induced nephrotoxicity.
Additionally, antifolate drugs may be a direct toxicant for renal tubules.
For patients on high-dose methotrexate treatment there is a risk for hyperbilirubinemia in acute increases in hepatic enzyme levels.
Elevated levels typically are of limited duration, returning to normal within about 10 days.
For some treatment protocols, methotrexate is given along with radiation therapy.8
Such combinations appeared increase likelihood of soft tissue necrosis and osteonecrosis.
Initially high-dose methotrexate treatment incorporated an idea of selective normal tissue rescue through the use of reduce folate leukovorin.
High-dose methotrexate however may also be effective in mitigating resistance mechanisms due to:
Damaged active transport
Reduced dihydrofolate reductase (target) affinity for methotrexate
Increased dihydrofolate reductase concentrations due to gene amplification as well as by
Reduced polyglutamation of methotrexate.8
Methotrexate administration may also be associated with additional side effects/toxicities including: 1
Allergic, interstitial pneumonitis
Defective oogenesis or spermatogenesis
Acute Lymphoblastic Leukemia in Children:1
Alverson B Leukemin in Children https://www.youtube.com/watch?v=KOMGMZeqqgA (5/2019)
Lecturio Medical Youtube Channel: https://www.youtube.com/channel/UCbYmF43dpGHz8gi2ugiXr0Q
NEJM video Targeting Cancer: The Story of Leukemia https://www.youtube.com/watch?v=bSuwwRi0GHI (4/2012)
NEJMvideo Youtube Channel: https://www.youtube.com/channel/UCqO3GxVYutcugyknCWdAcUA
Methotrexate is an especially important drug for managing childhood occurrences of acute lymphoblastic leukemia (ALL).
Usefulness of high-dose methotrexate includes:
Induction of remission
Maintenance of remission.
In this setting, ALL is considered a highly curable malignancy.
Specific dosing protocols are associated with induction, including leukovorin rescue and maintenance treatment.
In children treatment outcome appears inversely associated with the rate of drug clearance.
During methotrexate infusion, relatively higher study-state concentrations appear correlated with a decreased likelihood of leukemia relapse rates.
By contrast, in acute myelogenous leukemia (AML), methotrexate has much more limited usefulness with the exception of treating and prevention of leukemic meningitis.
For treatment for prevention of meningeal leukemia or lymphoma and for treatment of meningeal carcinomatosis methotrexate may be employed by the intrathecal route of administration.
Using this approach, high concentrations of methotrexate in the CSF can be obtained and the treatment appears effective even in those patients exhibiting systemic disease which exhibits resistance to methotrexate.
Methotrexate is also useful in choriocarcinoma treatment and in this context the drug is administered by the intramuscular route in a manner that allows alternating administration with leukovorin.1
Methotrexate may also be combined with other chemotherapeutic drugs.1
For example, methotrexate is part of combination treatment for Burkett and other non-Hodgkin lymphomas.
Breast carcinoma, head and neck cancer, ovarian cancer and bladder cancer also benefit by protocols that include methotrexate.
High-dose methotrexate with leukovorin rescue (HDM-L) is considered standard for adjuvant treatment of osteosarcoma and is associated with a high response rate in CNS lymphoma.
Administration of high-dose methotrexate with leukovorin may cause renal toxicity due to drug precipitation in acidic tubular fluid.
This adverse effect may be mitigated by prophylactic vigorous hydration and urinary alkalinization.1
Methotrexate: Primary Therapeutic Applications8
Primary CNS Lymphoma
Acute Lymphoblastic Leukemia
Breast Cancer, Bladder Cancer
Gestational Trophoblastic Cancer