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Decreased intestinal absorption of methotrexate in the rat following repeated oral dosing
Abstract:
The absorption of methotrexate (MTX) following single and repeated oral administrations was investigated in the rat and compared with that after intravenous injections. The absorption of intermediate dose MTX was poor (14.7%), both after single gift (25 mg X kg-1) and when given repeatedly at 72-hour intervals (3 X 25 mg X kg-1). Repeated oral administration did not produce higher plasma concentrations of MTX in spite of decreased elimination as a result of impaired renal clearance. It is concluded from these experiments that repeated oral administration of MTX when spaced 72 hours apart leads to a deterioration of the already incomplete intestinal absorption of the drug in the rat.
Insights
Oral methotrexate (MTX) absorption in rats is poor and worsens with repeated dosing. Even with impaired clearance, repeated oral MTX did not increase plasma levels, indicating reduced intestinal absorption over time.
Area of Science:
- Pharmacokinetics
- Drug Absorption
- Toxicology
Background:
- Methotrexate (MTX) is a crucial chemotherapy agent.
- Understanding MTX oral bioavailability is vital for effective treatment regimens.
- Previous studies suggest variable oral absorption of MTX.
Purpose of the Study:
- To investigate the oral absorption of methotrexate in rats after single and repeated administrations.
- To compare oral MTX absorption with intravenous administration.
- To evaluate the impact of repeated dosing intervals on MTX absorption and plasma concentrations.
Main Methods:
- Oral and intravenous administration of MTX in rats.
- Dosing regimens included single and repeated doses (72-hour intervals).
- Plasma MTX concentrations and renal clearance were monitored.
Main Results:
- Poor oral absorption of MTX (14.7%) was observed after single and repeated doses.
- Repeated oral administration did not enhance plasma MTX concentrations.
- Impaired renal clearance did not lead to higher plasma MTX levels with repeated oral dosing.
Conclusions:
- Oral administration of MTX in rats results in incomplete intestinal absorption.
- Repeated oral MTX dosing at 72-hour intervals exacerbates the initial poor absorption.
- The study highlights the limitations of oral MTX delivery in rats, even with compromised renal function.