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Alterations in methotrexate pharmacokinetics by naproxen in the rat as measured by microdialysis
P O Ekstrøm1, K E Giercksky, A Andersen
1Department of Surgical Oncology, The Norwegian Radium Hospital, Oslo. p.o.ekstrom@klinmed.uio.no
Abstract:
Reports of a potentially life-threatening interaction between the antifolate methotrexate (MTX) and drugs belonging to the NSAID class instigated a study of MTX pharmacokinetics by a microdialysis technique in the presence and absence of the NSAID naproxen in anesthetized rats. After pretreatment with naproxen, the animals received either 750 or 1,000 mg/kg MTX as a 6 h continuous intravenous infusion. During infusions, microdialysis effluents were obtained from probes situated intravenously, intrahepatically and intrarenally. In all three compartments, time-concentration AUCs for both MTX and its major extracellular metabolite, 7-hydroxymethotrexate (7-OH-MTX), increased about two-fold in the presence of naproxen. The mechanisms responsible for the MTX-NSAID interaction are briefly discussed. The study demonstrate that the microdialysis technique offers a means to investigate pharmacokinetic drug-drug interactions.
Insights
Naproxen, a nonsteroidal anti-inflammatory drug (NSAID), significantly increases methotrexate (MTX) levels in rats. This pharmacokinetic interaction, studied using microdialysis, highlights potential risks when combining these medications.
Area of Science:
- Pharmacology
- Toxicology
- Drug Interactions
Background:
- Reports suggest a dangerous interaction between methotrexate (MTX) and nonsteroidal anti-inflammatory drugs (NSAIDs).
- Understanding this interaction is crucial for patient safety.
Purpose of the Study:
- To investigate the pharmacokinetic interaction between MTX and naproxen in rats.
- To quantify changes in MTX and its metabolite concentrations in the presence of naproxen.
Main Methods:
- Utilized microdialysis technique in anesthetized rats.
- Administered MTX (750 or 1,000 mg/kg) intravenously over 6 hours.
- Collected microdialysis samples from intravenous, hepatic, and renal compartments.
Main Results:
- Naproxen pretreatment led to a two-fold increase in the area under the concentration-time curve (AUC) for MTX.
- Concentrations of the major metabolite, 7-hydroxymethotrexate (7-OH-MTX), also doubled in all compartments.
- Observed interaction in intravenous, intrahepatic, and intrarenal compartments.
Conclusions:
- Naproxen significantly alters MTX pharmacokinetics, increasing drug and metabolite exposure.
- The microdialysis technique is effective for studying drug-drug interactions.
- Findings suggest caution when co-administering MTX and NSAIDs like naproxen.