メトトレキサート
メトトレキサート（MTX）は強力な**葉酸拮抗薬**であり、獣医腫瘍学において主に犬や猫の**リンパ増殖性疾患**（リンパ腫など）および一部の固形腫瘍の治療に使用されます。 抗悪性腫瘍特性に加えて、顕著な**免疫抑制**作用も持ち合わせており、標準的なプレドニゾロンやクロラムブシル治療に反応しない猫の非化膿性胆管炎/胆管肝炎などの難治性免疫介在性疾患に対する貴重な選択肢となります。 **臨床のポイント：** MTXは治療域が非常に狭く、腎クリアランスに大きく依存しているため、重篤な毒性を防ぐためには患者の水分補給と腎機能の維持が極めて重要です。急速に分裂する細胞に対して強い毒性を示すため、消化管上皮や骨髄は特に巻き添え被害を受けやすくなります。
作用機序: Methotrexate is an **S-phase specific antimetabolite**. It acts by competitively and irreversibly inhibiting the enzyme **dihydrofolate reductase (DHFR)**. * Folic acid → (via DHFR) → Dihydrofolate → (via DHFR) → **Tetrahydrofolate** (active form). * By blocking DHFR, MTX prevents the reduction of dihydrofolate to tetrahydrofolate. * Tetrahydrofolate is an essential cofactor for the synthesis of purines and pyrimidines (specifically thymidylate). * The depletion of these precursors halts DNA, RNA, and protein synthesis, ultimately leading to apoptosis in rapidly proliferating cells (e.g., neoplasms, bone marrow, GI tract epithelium). > **Note:** DHFR has a much greater affinity for MTX than for folic acid. Therefore, coadministration of folic acid will not reverse MTX toxicity. **Leucovorin calcium** (a derivative of tetrahydrofolic acid that bypasses the blocked enzyme) is required as a rescue agent.
動物種別の用量
- For susceptible neoplastic diseases (usually as part of a multi-drug protocol) · 2.5 mg/m2 PO 2-3 times weekly; 0.3-0.8 mg/m2 IV every 7 days · PO/IV · 2-3 times weekly (PO) or every 7 days (IV)
- For non-suppurative cholangitis/cholangiohepatitis (CCHC) syndrome with fibrosis · A total dose of 0.4 mg per cat total dose given on one day in three divided doses: 0.26 mg at hour zero, 0.13 mg at the 12 and 24 hour dosing. Repeat every 7-10 days. · PO · Divided over 24 hours, repeated every 7-10 days · Use in conjunction with ursodeoxycholic acid (15 mg/kg PO q24h) and folate (0.25 mg/kg PO q24h).
- As part of the LMP protocol for maintenance of canine lymphoma · 2.5-5 mg/m2 PO twice a week · PO · twice a week · Given with Chlorambucil 20 mg/m2 PO every 15 days and Prednisone 20 mg/m2 PO every other day. When Vincristine is added it is at a dose of 0.5-0.7 mg/m2 and is given every 15 days alternating weeks with the chlorambucil.
- In combination with other antineoplastics (per protocol) · 5 mg/m2 PO twice weekly or 0.8 mg/kg IV every 21 days; alternatively 2.5 mg/m2 PO daily · PO/IV · twice weekly, every 21 days, or daily
用量は獣医療従事者向けの臨床リファレンスです。必ず最新の添付文書と個々の患者で確認してください。
投与経路
禁忌
- Preexisting bone marrow depression
- Severe hepatic insufficiency
- Severe renal insufficiency
- Hypersensitivity to the drug
- Pregnancy (Teratogenic/Embryotoxic - FDA Category X)
- Nursing mothers
- Pre-existing severe bone marrow suppression
- Severe renal impairment
- Severe hepatic impairment
- Pregnancy and lactation (teratogenic and embryotoxic)
- Patients with significant third-space fluid accumulations (e.g., ascites, pleural effusion)
有害事象
- Diarrhea
- Nausea
- Vomiting
- Inappetence (especially in cats)
- GI toxicity (ulcers, mucosal sloughing, stomatitis)
- Hematopoietic toxicity / Myelosuppression (nadir at 4-6 days)
- Hepatopathy
- Renal tubular necrosis
- Alopecia
- Depigmentation
- Pulmonary infiltrates and fibrosis
- CNS toxicity (encephalopathy) if given intrathecally
- Anaphylaxis (rare)
- Myelosuppression (neutropenia, thrombocytopenia, anemia)
- Gastrointestinal toxicity (anorexia, vomiting, diarrhea, stomatitis)
- Hepatotoxicity (elevated liver enzymes)
薬物相互作用
- Amiodarone · Prolonged PO administration (>2 weeks) may inhibit MTX metabolism
- Asparaginase · Given concomitantly with MTX may decrease MTX efficacy
- Azathioprine · Potential for increased risk for hepatic toxicity
- Chloramphenicol · May displace MTX from plasma proteins increasing risk for toxicity, but also may reduce MTX absorption and enterohepatic recirculation
- Cisplatin · May have synergistic action with MTX, but alter the renal elimination of MTX
- Cyclosporine · May increase MTX levels
- Folic Acid · May reduce MTX efficacy, but folate deficiency increases MTX toxicity
- Neomycin (oral) · May decrease the absorption of oral methotrexate if given concomitantly
- NSAIDs / Salicylates · Severe hematologic and GI toxicity risk; use caution in dogs also on MTX
- Penicillins · May decrease MTX renal elimination · moderate
- Probenecid · May inhibit the tubular secretion of MTX and increase its half-life · major
- Pyrimethamine · A similar folic acid antagonist; may increase MTX toxicity and should not be given to patients receiving MTX
モニタリング
- Efficacy of treatment
- Clinical signs of GI irritation and ulceration
- Complete blood counts (with platelets) weekly early in therapy, then every 4-6 weeks (Discontinue if WBC <4000/mm3 or platelets <100,000/mm3)
- Baseline and ongoing renal function tests
- Baseline and ongoing hepatic function tests (liver enzymes)
- Complete Blood Count (CBC) - baseline and prior to each dose (monitor for nadir)
- Renal function panel (BUN, Creatinine, Urinalysis)
- Hepatic enzymes (ALT, AST, ALP, Bilirubin)
- Clinical signs of gastrointestinal toxicity (vomiting, diarrhea, anorexia)
- Hydration status
過量投与
Acute overdosage in dogs is associated with severe exacerbations of adverse effects, particularly **myelosuppression** and **acute renal failure**. Acute tubular necrosis occurs secondary to drug precipitation in the renal tubules. * **Toxicity Thresholds:** In dogs, the maximally tolerated dose is reported to be 0.12 mg/kg q24h for 5 days. A dose of 10 mg/kg is considered lethal if leucovorin rescue is not performed. * **Decontamination:** Empty the gut and prevent absorption using standard protocols if ingestion is recent. Oral neomycin has been suggested to help prevent intestinal absorption. * **Renal Protection:** Forced alkaline diuresis should be considered to minimize renal damage. Maintain urine pH between 7.5-8 by adding 0.5-1 mEq/kg of sodium bicarbonate per 500 mL of IV fluid. * **Antidote:** **Leucovorin calcium** is the specific therapy for MTX overdoses. It must be given as soon as possible (preferably within the first hour, definitely within 48 hours). Dogs treated with leucovorin at 15 mg/m2 every 3 hours IV for 8 doses, then IM q6h for 8 doses were able to tolerate very high MTX doses.
VetSheet の薬剤リファレンスは、獣医療従事者向けの臨床意思決定支援を目的としており、専門的判断やメーカーの最新添付文書に代わるものではありません。