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Effect of indomethacin on the pharmacokinetics of methotrexate in rabbits
T A Najjar1, A R Morad, R M Khan
1Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyad, Saudi Arabia.
Abstract:
The interaction between indomethacin (IND) and methotrexate (MTX) was investigated in rabbits. The study was designed so as to evaluate the effect of IND (1 mg h-1) during a continuous MTX infusion (1 x 2 mg kg-1) over 240 min. IND was injected i.v. at hourly intervals after a steady state MTX concentration had been established. Plasma MTX concentration before and after IND did not differ significantly (p greater than 0.05). The elimination half-life (t1/2 beta) calculated during the washout interval (mean +/- SD) was 47 x 4 +/- 21 x 5 min which is close to that calculated in a reference group of rabbits. This excludes the possibility of delayed elimination as responsible for this toxicity. The toxicity of this combination was confirmed despite the absence of significant pharmacokinetic changes. It is possible that the toxic interaction was caused by enhanced cytotoxic effect of MTX.
Insights
Indomethacin (IND) did not alter methotrexate (MTX) pharmacokinetics in rabbits, yet toxicity persisted. This suggests the drug interaction may stem from an enhanced cytotoxic effect of MTX, not altered drug elimination.
Area of Science:
- Pharmacology
- Toxicology
- Drug Interactions
Background:
- Methotrexate (MTX) is a crucial chemotherapy agent.
- Indomethacin (IND) is a nonsteroidal anti-inflammatory drug.
- Concurrent administration of IND and MTX can lead to toxicity.
Purpose of the Study:
- To investigate the pharmacokinetic interaction between indomethacin and methotrexate in rabbits.
- To determine if indomethacin affects methotrexate elimination.
- To explore the mechanism behind the observed toxicity of the IND-MTX combination.
Main Methods:
- Rabbits received a continuous infusion of methotrexate (MTX).
- Indomethacin (IND) was administered intravenously after MTX steady-state concentrations were achieved.
- Plasma MTX concentrations and elimination half-life were measured before and after IND administration.
Main Results:
- Plasma MTX concentrations did not significantly change after IND administration (p > 0.05).
- The elimination half-life of MTX remained comparable to control groups.
- Toxicity associated with the IND-MTX combination was observed despite unchanged pharmacokinetics.
Conclusions:
- Indomethacin does not significantly alter the pharmacokinetics or elimination of methotrexate in rabbits.
- The observed toxicity of the indomethacin-methotrexate combination is unlikely due to delayed MTX elimination.
- The interaction may involve an enhanced cytotoxic effect of methotrexate, independent of pharmacokinetic changes.