The effect of organic acids on renal clearance of methotrexate in man

Liegler, Donald G.; Henderson, Edward S.; Hahn, A B Mary Anne; Oliverio, Vincent T.

doi:10.1002/cpt1969106849

Cited by 255 publications

(60 citation statements)

References 6 publications

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“…Several studies of methotrexate have documented decreases in total systemic clearance and corresponding increases in AUC with coadministration of salicylates (11,19,20); however, all of the positive methotrexate-aspirin drug interaction studies used higher doses of aspirin than our current clinical trial. Other studies evaluating the effects of ibuprofen on methotrexate kinetics have provided inconsistent results and thus offer little context for interpreting the influence of ibuprofen on pemetrexed clearance (22,23).…”

Section: Discussionmentioning

confidence: 77%

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Two Drug Interaction Studies Evaluating the Pharmacokinetics and Toxicity of Pemetrexed When Coadministered with Aspirin or Ibuprofen in Patients with Advanced Cancer

Sweeney

Takimoto

Latz

et al. 2006

Clinical Cancer Research

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Purpose: Pemetrexed is an antimetabolite that is structurally similar to methotrexate. Because nonsteroidal anti-inflammatory drugs (NSAID) impair methotrexate clearance and increase its toxicity, we evaluated the pharmacokinetics and toxicity of pemetrexed when coadministered with aspirin or ibuprofen in advanced cancer patients. Experimental Design: In two independent, randomized, crossover drug interaction studies, cancer patients with a creatinine clearance (CrCl) z60 mL/min received an NSAID (aspirin or ibuprofen) with either the first or the second dose of pemetrexed (cycle 1 or 2). Pemetrexed (500 mg/m 2 ) was infused i.v. on day 1 of a 21-day cycle, and all patients were supplemented with oral folic acid and i.m. vitamin B 12 . Aspirin (325 mg) or ibuprofen (400 mg; 2 Â 200 mg) was given orally every 6 hours, starting 2 days before pemetrexed administration, with the ninth and final dose taken 1 hour before infusion. Pemetrexed pharmacokinetics with and without concomitant NSAID treatment were compared for cycles 1and 2. Results: Data from 27 patients in each study were evaluable for the analysis of pemetrexed pharmacokinetics. Coadministration of aspirin did not alter pemetrexed pharmacokinetics; however, ibuprofen coadministration was associated with a 16% reduction in clearance, a 15% increase in maximum plasma concentration, and a 20% increase in area under the plasma concentration versus time curve but no significant change in V ss compared with pemetrexed alone. No febrile neutropenia occurred in any patient, and no increase in pemetrexed-related toxicity was associated with NSAID administration. Conclusions: Pemetrexed (500 mg/m 2 ) with vitamin supplementation is well tolerated and requires no dosage adjustment when coadministered with aspirin (in patients with CrCl z60 mL/min) or ibuprofen (in patients with CrCl z80 mL/min).Pemetrexed is a novel antifolate that inhibits three folatedependent enzymes involved in purine and pyrimidine synthesis: thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase (1). In preclinical studies, pemetrexed was effective against some methotrexateresistant cell lines (1, 2), suggesting that its mechanism of action may differ from that of classic antifolates. The drug has shown antitumor activity in a range of solid malignancies, including mesothelioma, non -small cell lung, bladder, head and neck, breast, cervical, colorectal, pancreatic, and gastric cancers (3, 4). Pemetrexed has received regulatory approval for the treatment of malignant pleural mesothelioma in combination with cisplatin and as single-agent therapy for second-line treatment of non -small cell lung cancer (5 -7).Pharmacokinetic evaluations for three phase I dose-escalation trials showed that pemetrexed is f80% protein bound, with rapid plasma distribution and elimination phases, and exhibits linear pharmacokinetics over a broad range of doses (0.2-838 mg/m 2 ). The steady-state volume of distribution (V ss ) of pemetrexed is small (16 L), suggesti...

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Section: Discussionmentioning

confidence: 77%

“…These NSAIDs are known to interact with some antifolates, such as methotrexate (10). Although the mechanism of interaction is unknown, NSAIDs may compete for renal tubular secretion with methotrexate (10,11), decreasing the renal clearance of methotrexate and increasing systemic exposure, which can lead to increased drug-induced toxicities.…”

mentioning

confidence: 99%

Two Drug Interaction Studies Evaluating the Pharmacokinetics and Toxicity of Pemetrexed When Coadministered with Aspirin or Ibuprofen in Patients with Advanced Cancer

Sweeney

Takimoto

Latz

et al. 2006

Clinical Cancer Research

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“…• Inhibition of the cytochrome P450 system (2C8 and 2C9) 22 • Renal drug transporter inhibition (organic cation transporter and organic anion transporter) 23,24 Polypharmacy Common S Sugar Hypoglycemia [25][26][27][28][29][30] • Renal insufficiency 25 • High-dose trimethoprimsulfamethoxazole 25 • Concomitant use of sulphonylureas or meglitinides [26][27][28][29][30] Common as a drug-drug interaction; rare when trimethoprimsulfamethoxazole is used in isolation Common Hyperkalemia [31][32][33][34][35][36][37] • Renal insufficiency 34,35 • High-dose trimethoprimsulfamethoxazole 32,35 • Older age 34 • Diabetes 34 • AIDS 39 • Concomitant use of ACE inhibitors, angiotensin receptor blockers, spironolactone or NSAIDs 36,37 Acute interstitial nephritis 15 …”

Section: Interactions With Other Drugsmentioning

confidence: 99%

“…61,62 Interactions involving drug transporters Trimethoprim also inhibits the renal organic cation transporter and sulfamethoxazole inhibits the organic anion transporter, 68,69 transport systems that normally facilitate the renal elimination of several drugs. In children receiving methotrexate, treatment with trimethoprim-sulfamethoxazole decreases organic anion transporter-mediated renal clearance of methotrexate by 40%, 23,24 increasing the risk of methotrexate toxicity (including cytopenia, mucositis, hepatotoxicity and gastrointestinal symptoms). The anti-folate effect of trimethoprim may also contribute to this interaction, as documented in several case reports and one observational study.…”

Section: Interactions Involving the Cytochrome P450 Enzyme Systemmentioning

confidence: 99%

Considerations when prescribing trimethoprim-sulfamethoxazole

Ho¹,

Juurlink²

2011

Canadian Medical Association Journal

185

137

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“…A likely site of capacity limited elimination is the proximal convo- (Liegler, Henderson, Hahn & Oliverio, 1969).…”

mentioning

confidence: 99%

Methotrexate kinetics: dose dependent change in clearance following bolus i.v. injection [proceedings]

Lawrence¹,

McVie²,

Steele³

et al. 1980

Brit J Clinical Pharma

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The effect of organic acids on renal clearance of methotrexate in man

Abstract: Methotrexate ( MTX), a folic acid antagonist, is extensively used in the treatment of neoplastic diseases. It has been shown that the major method of elimination of this drug in man is renal excretion, since over 95 per cent of a parenterally

Cited by 255 publications

References 6 publications

Two Drug Interaction Studies Evaluating the Pharmacokinetics and Toxicity of Pemetrexed When Coadministered with Aspirin or Ibuprofen in Patients with Advanced Cancer

Two Drug Interaction Studies Evaluating the Pharmacokinetics and Toxicity of Pemetrexed When Coadministered with Aspirin or Ibuprofen in Patients with Advanced Cancer

Considerations when prescribing trimethoprim-sulfamethoxazole

Methotrexate kinetics: dose dependent change in clearance following bolus i.v. injection [proceedings]

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