Methotrexate leucovorin

O van Tellingen, HR van der Woude, JH Beijnen, CJT van Beers, WJ Nooyen. Stable and sensitive method for the simultaneous determination of N -methyltet-rahydrofolate, leucovorin, methotrexate and 7-hydroxymethotrexate in biological fluids. J Chromatogr 488 379-388, 1989. 

LEUCOVORIN. When leucovorin is administered after a large dose of methotrexate, the timing of tiie administration is outlined by tiie primary health care provider. It is essential that the leucovorin be given at tiie exact time ordered because tiie purpose of folinic acid rescue is to allow a high dose of a toxic drug to remain in tiie body for only a limited time... 

Leucovorin 10 mg PO q6hours, 24 hours following methotrexate x 8 doses... 

Leucovorin (folinic acid) - enzyme cofactor for thymidylate synthase rescues from methotrexate toxicity potentiates cytotoxicity of fluoro— pyrimidines -occasional nausea -skin rash -headache -rare allergic reactions... 

III. The answer is d, (Hardman, pp 1247, L135.) Leucovorin prevents methotrexate from inhibiting dihydrofolate reductase and reverses all of its adverse effects except neurotoxicity... 

The answer is c. (Katzung, pp 608-609, 932-9.13.) Methotrexate is classified as an anti metabolite with therapeutic uses in cancer chemotherapy and as an immunosuppressive agent indicated in the treatment of severe active classical rheumatoid arthritis. Leucovorin is related to methotrexate in that it is an antagonist of its actions. It can supply a source of reduced folate for the methylation reactions that are prevented by methotrexate. 

An electron impact mass spectrum of calcium leuco-vorin has not been obtained because the compound is not sufficiently volatile. It would be difficult to isolate the free acid without first dehydrating the compound. Due to its ionic nature, calcium leucovorin will not dissolve in common silylating reagents. Field desorption, another mass spectral technique, generally lends itself more to compounds like leucovorin. Indeed, this technique has been applied successfully to methotrexate and other folic acid analogs.1 ... 

Recently a great deal of effort has been spent in studying the metabolism of leucovorin in vivo. This emphasis was prompted by the chemical stability of this folate and by the observation of a reduction in toxicity of methotrexate when it was given in conjunction with leucovorin. Fol-inic acid is found in human liver, but it is not the major circulating folate, which is 5-methyltetrahydrofolate. 

Oral and parenteral Leucovorin rescue after high-dose methotrexate therapy in osteosarcoma. 

Leucovorin rescue after high-dose methotrexate therapy The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 g/m administered by IV infusion over 4 hours. Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m ) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. In the presence of Gl toxicity, nausea, or vomiting, administer leucovorin parenterally. 

If significant clinical toxicity is observed, extend leucovohn rescue for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. Impaired methotrexate elimination or inadvertent overdosage Beg n leucovorin rescue as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion (see Warnings). Administer leucovorin 10 mg/m IV, IM, or orally every 6 hours until the serum methotrexate level is less than 10 M. In the presence of Gl toxicity, nausea, or vomiting, administer leucovorin parenterally. 

Determine serum creatinine and methotrexate levels at 24-hour intervals. If the 24-hour serum creatinine has increased 50% over baseline or if the 24 or 48 hour methotrexate level is greater than 5 x 10 M or greater than 9 x lO M, respectively, increase the dose of leucovorin to 100 mg/m IV every 3 hours until the methotrexate level is less than 10 M. 

Pharmacology Leucovorin is one of several active, chemically reduced derivatives of folic acid. It is useful as an antidote to drugs that act as folic acid antagonists. Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. 

Therapy with leucovorin/5-FU must not be initiated or continued in patients who have symptoms of Gl toxicity of any severity, until those symptoms have completely resolved. Patients with diarrhea must be monitored with particular care until the diarrhea has resolved, as rapid clinical deterioration leading to death can occur. Methotrexate concentrations Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin. Delayed methotrexate excretion may be caused by a third space fluid accumulation, renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of leucovorin or prolonged administration may be indicated. Doses higher than those recommended for oral use must be given IV. 

Folic acid antagonist overdosage In the treatment of accidental overdosages of folic acid antagonists, administer leucovorin as promptly as possible. As the time interval between antifolate administration (eg, methotrexate) and leucovorin rescue increases, leucovorin s effectiveness in counteracting toxicity decreases. 

Leucovorin calcium Wellcovorin) Folic acid antagonists (eg, methotrexate)... 

Clinically significant sensitivity to trimetrexate, leucovorin, or methotrexate. 

Merlano and colleagues completed a phase III study comparing sequential vs alternating chemoradiotherapy (62). One hundred sixteen patients were randomized to arm A of the sequential regimen of four cycles of Vinblastine (6 mg/m2, h 0), bleomycin (30 mg, h 6), methotrexate (200 mg, h 24-26), and leucovorin (45 mg, h 48) followed within 3 wk by definitive radiotherapy or arm B composed of the same chemotherapy regimen alternating with three courses of daily fractionated therapy for 2 wk. The difference in response rates (52% for arm A vs 64.9% for arm B) was found to be statistically significant, p < 0.03, as well as the median PFS (26 vs 34 wk, p = 0.046) without differences seen in OS (p = 0.64). 

The adverse effects of methotrexate include gastrointestinal complaints, bone marrow suppression, alopecia and nephrotoxicity. The toxic effects of methotrexate may be terminated by administering the fully reduced folate coenzyme leucovorin (folinic acid). Leucovorin rescue permits the administration of high doses of methotrexate, for example in situations where partially resistance has occurred or to obtain cytotoxic concentrations of methotrexate in the CNS. 

High-dose methotrexate administration with leucovorin rescue has produced remissions in 30% of patients with metastatic osteogenic sarcoma. 

Plasma methotrexate concentrations as a therapeutic guide to high-dose methotrexate therapy with leucovorin rescue continue leucovorin until plasma methotrexate concentrations are <5 X 10 M (see dosage)... 

It is used as leucovorin calcium (calcium folinate). It is 5-formyl derivative of tetrahydrofolic acid and it acts as an antidote to folic acid antagonists like methotrexate or pyrimethamine which inhibit the enzyme dihydrofolate reductase. 

Nausea and mucosal ulcers are the most common toxicities. Progressive dose-related hepatotoxicity in the form of enzyme elevation occurs frequently, but cirrhosis is rare (< 1%). Liver toxicity is not related to serum methotrexate concentrations, and liver biopsy follow-up is only recommended every 5 years. A rare hypersensitivity-like lung reaction with acute shortness of breath is documented, as are pseudolymphomatous reactions. The incidence of gastrointestinal and liver function test abnormalities can be reduced by the use of leucovorin 24 hours after each weekly dose or by the use of daily folic acid, although this may decrease the efficacy of the methotrexate. This drug is contraindicated in pregnancy. 

Methotrexate acts by inhibition of dihydrofolate reductase, the enzyme requisite for the reduction of dihydrofolic acid (3) to 5,6,7,8-tetrahydrofolic acid (4). In turn, (4) is a precursor to a series of enzyme cofactors (5-7) essential for the transfer of one carbon unit necessary for the biosynthesis of purines and pyrimidines and hence, ultimately, DNA. As an inhibitor of dihydrofolate reductase, methotrexate kills cells during the S phase of the cell cycle, when the cells are in the log phase of growth. Unfortunately, this cytotoxicity is non-selective, and rapidly proliferating normal cells, e.g., gastrointestinal epithelium cells and bone marrow, are dramatically affected as well. In addition, recent use of high dose methotrexate therapy with leucovorin rescue has led to additional clinical problems arising from a dose-related nephrotoxic metabolite, 7-hydroxy methotrexate (8). Finally, the very polar nature of methotrexate renders it virtually impenetrable to the blood-brain barrier, which can necessitate direct intrathecal injection in order to achieve therapeutic doses for the treatment of CNS tumours. 

The effects of methotrexate may be reversed by the administration of leucovorin, the reduced folate. This leucovorin rescue prevents or reduces the toxicity of methotrexate, which is expressed as mouth lesions (stomatitis), injury to the gastrointestinal epithelium (diarrhea), leukopenia, and thrombocytopenia (see Chapter 62). 

CMF Cyclophosphamide, methotrexate, fluorouracil COP Cyclophosphamide, vincristine (oncovin), prednisone FAC Fluorouracil, doxorubicin (adriamycin), cyclophosphamide FEC Fluorouracil, epirubicin, cyclophosphamide IFL Irinotecan, fluorouracil, leucovorin MP Melphalan, prednisone... 

Methotrexate is administered by the intravenous, intrathecal, or oral route. Up to 90% of an oral dose is excreted in the urine within 12 hours. The drug is not subject to metabolism, and serum levels are therefore proportionate to dose as long as renal function and hydration status are adequate. Dosages and toxic effects are listed in Table 55-3. The effects of methotrexate can be reversed by administration of leucovorin (citrovorum factor). Leucovorin rescue has been used with accidental overdose or experimentally along with high-dose methotrexate therapy in a protocol intended to rescue normal cells while still leaving the tumor cells subject to its cytotoxic action. 

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