What is known about drug interactions between methotrexate and norfloxacin, tramadol or paracetamol

Fråga: What is known about drug interactions between methotrexate and norfloxacin, tramadol or paracetamol?

The question concerns a female patient with RA who is currently being treated with methotrexate. The patient has developed pyelonephritis and addition of norfloxacin, tramadol and paracetamol is considered. Can any of these drugs interact with methotrexate?

Sammanfattning: No data on drug interactions between methotrexate, norfloxacin, tramadol or paracetamol were found. Theoretically, norfloxacin being a weak organic acid might inhibit the clearance of methotrexate. In vitro studies have shown that methotrexate increases the liver toxicity of paracetamol, but the clinical relevance of this is unknown. Methotrexate concentrations can be monitored in cases where drug interactions are suspected.

Svar: Methotrexate and norfloxacin: no earlier reports on drug interactions between methotrexate and norfloxacin were found. However, a number of weak organic acids have been shown to inhibit the tubular secretion of methotrexate (1). Since norfloxacin is a weak organic acid, this possibility should be kept in mind.

Methotrexate and tramadol: no data on interactions between methotrexate and tramadol was found. Tramadol is a newly introduced drug and our experience is still limited with it. Considering the fact that methotrexate is mainly eliminated unchanged via the kidneys (up to 90 percent) whereas tramadol is extensively metabolised by the liver (2), the risk of a significant pharmacokinetic interaction is probably low.

Methotrexate and paracetamol: No data on drug interactions between methotrexate and paracetamol was found. Paracetamol is largely eliminated in the form of metabolites, primarily as conjugates. A small proportion of paracetamol undergoes cytochrome P450-mediated N-hydroxylation to form a toxic metabolite which normally reacts with glutathione (2). In an in-vitro study where the toxicity of methotrexate was investigated in cultured chicken hepatocytes, methotrexate increased paracetamol toxicity by decreasing glutathione levels (3). 1 FASS 1999 (The Swedish catalogue of approved medical products) 2 Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Goodman Gilman A, editors. Goodman & Gilman´s The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996 3 Lindenthal J, Sinclair JF, Howell S, Cargill I, Sinclair PR, Taylor T: Toxicity of paracetamol in cultured chick hepatocytes treated with methotrexate. Eur J Pharmacol 1993; 228: 289-298