Alterations in methotrexate pharmacokinetics by naproxen in the rat as measured by microdialysis.
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.
Ekstrøm
P O
PO
Department of Surgical Oncology, The Norwegian Radium Hospital, Oslo. p.o.ekstrom@klinmed.uio.no
Giercksky
K E
KE
Andersen
A
A
Slørdal
L
L
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D005493:Folic Acid Antagonists / Q000097:blood; D006900:Hydroxylation; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D017551:Microdialysis; D009288:Naproxen / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D009288:Naproxen; C011864:7-hydroxymethotrexate; D008727:Methotrexate