Methotrexate excretion

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. 

Methotrexate [P] Decreased renal methotrexate excretion possible methotrexate toxicity. 

Two patients treated with a chemotherapy regimen containing high-dose methotrexate, cisplatin, doxorubicin and ifosfamide had delayed methotrexate excretion and methotrexate toxicity during a cycle soon after they had received vancomycin. Methotrexate levels took 170 to 231 hours to fall to 200 micromol/mL, and toxicity (mucositis) occurred. Subclinical... 

For the effeets of aeidie urine on methotrexate excretion see Methotrexate + Aseorhie aeid (Vitamin C) , p.646. 

The drug is metabolized rapidly in the liver, kidney, intestinal mucosa, and even red blood cells. Therefore it has a plasma half-life of only 10 min after bolus intravenous application. The major metabolite, uracil arabinoside (ara-U), can be detected in the blood shortly after cytarabine administration. About 80% of the dose is excreted in the urine within 24 h, with less than 10% appearing as cytarabine the remainder is ara-U. After continuous infusion, cytarabine levels in the liquor (cerebro-spinal fluid) approach 40% of that in plasma. Continuous infusion schedules allow maximal efficiency, with uptake peaks of 5-7 pM. It can be administered intrathecally as an alternative to methotrexate. 

The co-administration of drugs which inhibit the transporters involved in renal tubular secretion can reduce the urinaty excretion of drugs which are substrates of the transporter, leading to elevated plasma concentrations of the drugs. For example, probenecid increases the plasma concentration and the duration of effect of penicillin by inhibiting its renal tubular secretion. It also elevates the plasma concentration of methotrexate by the same mechanism, provoking its toxic effects. 

If the unbound drug concentrations in plasma are higher than their K values on the transporters, then transporter function may be significantly affected [106], Following a pharmacokinetic analysis of the effect of probenecid on the hepatobiliary excretion of methotrexate, it has been shown the extent of an in vivo drug-drug interaction can be quantitatively predicted from the kinetic parameters for transport across the sinusoidal and bile canalicular membranes determined in vitro [107]. 

Ueda, K., Kato, Y., Komatsu, K., Sugiyama, Y., Inhibition of biliary excretion of methotrexate by probenecid in rats quantitative prediction of interaction from in vitro data, J. Pharmacol. Exp. Ther. 2001,... 

Concomitant administration of methotrexate and Voltarol, a proprietary preparation of diclofenac, a non-steroidal anti-inflammatory drug, may result in accumulation of methotrexate as its excretion is reduced. The use of diclofenac and diuretics such as bendroflumethiazide may increase the risk of nephrotoxicity. Concomitant use of alcohol and an angiotensin-converting enzyme inhibitor such as lisinopril (Zestril) may result in an enhanced hypotensive effect. Alcohol and the benzodiazepine diazepam (Valium) may result in enhanced sedation. 

Methotrexate is an antimetabolite drug that is excreted primarily by the kidney. It is contraindicated in significant renal impairment and in hepatic impairment. It is nephrotoxic and accumulation may occur in renal impairment. Dose should be reduced in renal impairment that is not severe and drug should be avoided if creatinine clearance is less than 20 mL/minute. 

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. 

Methotrexate is well absorbed orally and at usual dosages is 50% bound to plasma proteins. The plasma decay that follows an intravenous injection is triphasic, with a distribution phase, an initial elimination phase, and a prolonged elimination phase. The last phase is thought to reflect slow release of methotrexate from tissues. The major routes of drug excretion are glomerular filtration andl active renal tubular secretion. 

Methotrexate Aspirin, phenylbutazone, probenecid Delayed excretion Increased toxicity. 

The drug is approximately 70% absorbed after oral administration (see Chapter 54). It is metabolized to a less active hydroxylated metabolite, and both the parent compound and the metabolite are polyglutamated within cells, where they stay for prolonged periods. Methotrexate s serum half-life is usually only 6-9 hours, although it may be as long as 24 hours in some individuals. Methotrexate s concentration is increased in the presence of hydroxychloroquine, which can reduce the clearance or increase the tubular reabsorption of methotrexate. This drug is excreted principally in the urine, but up to 30% may be excreted in bile. 

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. 

Masuda M, I lzuka Y, Yamazaki M, et al. Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats. Cancer Res 1997 57 (16) 3506-3510. 

As more than 80% of methotrexate is excreted unchanged in the kidneys, a minor decrease in renal function can have a profound effect on the renal clearance of methotrexate and lead to significant toxicity, When drugs that impair the renal clearance of methotrexate are used concurrently, it is mandatory to measure methotrexate levels. 

METHOTREXATE ANTIVIRALS -OSELTAMIVIR Possible t efficacy/toxicity Competition for renal excretion Monitor more closely for signs of immunosuppression. Predicted interaction... 

Interference with active transport. Organic acids are passed from the blood into the urine by active transport across the renal tubular epithelium. Penicillin is mostly excreted in this way. Probenecid, an organic acid that competes successfully with penicillin for this transport system, may be used to prolong the action of penicillin when repeated administration is impracticable, e.g. in sexually transmitted diseases, where compliance is notoriously poor. Interference with renal excretion of methotrexate by aspirin, of zidovudine by probenecid and of digoxin by quinidine, contribute to the potentially harmful interactions with these combinations. 

Cytotoxics renal tubular excretion of methotrexate is reduced by competition with NSAIDs, with risk of methotrexate toxicity (low-dose methotrexate given weekly avoids this hazard). 

Tubule obstruction. Given certain physicochemical conditions, crystals can deposit within the tubular lumen. Methotrexate, for example, is relatively insoluble at low pH and can precipitate in the distal nephron when the urine is acid. Similarly the uric acid produced by the metabolism of nucleic acids released during rapid tumour cell lysis can cause a fatal urate nephropathy. This was a particular problem with the introduction of chemotherapy for leukaemias until the introduction of allopurinol it is now routinely given before the start of chemotherapy to block xanthine oxidase so that the much more soluble uric acid precursor, hypoxanthine, is excreted instead. Crystal-nephropathy is also a... 

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