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Disposition of 5-methyltetrahydrohomofolate and methotrexate in rats
Abstract:
The pharmacologic disposition of [methyl-14C]5-methyltetrahydrohomofolate (MTHHF) and [3H]methotrexate (MTX) has been studied in rats after iv doses of 25 mg/kg. Thin-layer chromatography and high-pressure liquid chromatography were used to separate the parent compounds from possible products. In rat serum, levels of MTHHF decreased with half-lives of 7 and 55 mins; for MTX, the corresponding values of half-lives were 14 and 54 mins. No metabolites of MTHHF or MTX were found in the samples assayed. At 3, 6, and 24 hrs after administration of MTHHF or MTX, liver, kidney, and small intestine contained concentrations of the drugs greater than those in serum. In rats with cannulated bile ducts, 16% of 60% of the doses of MTHHF and MTX, respectively, were excreted in the bile within 4 hrs. In 24 hrs, 51% of the dose of MTHHF and 41% of the dose of MTX were excreted in the urine of rats without bile cannulas. During the same time, fecal excretion accounted for 21% of the dose of MTHHF and 17% of the dose of MTX. The data indicate that enterohepatic circulation is probably extensive for MTX but less so for MTHHF.
Insights
Pharmacokinetic studies in rats reveal distinct elimination patterns for 5-methyltetrahydrohomofolate (MTHHF) and methotrexate (MTX). MTX exhibits more extensive enterohepatic circulation than MTHHF, influencing drug disposition.
Area of Science:
- Pharmacology
- Drug Metabolism
- Toxicology
Background:
- 5-methyltetrahydrohomofolate (MTHHF) and methotrexate (MTX) are folate analogs with distinct roles in cellular metabolism.
- Understanding their pharmacokinetic profiles is crucial for optimizing therapeutic applications and managing potential toxicities.
Purpose of the Study:
- To investigate and compare the pharmacologic disposition of MTHHF and MTX in rats.
- To elucidate the routes of excretion and potential for enterohepatic circulation of these compounds.
Main Methods:
- Rats received intravenous doses of radiolabeled MTHHF and MTX (25 mg/kg).
- Pharmacokinetic parameters were determined using thin-layer and high-pressure liquid chromatography.
- Excretion patterns were analyzed through bile and urine collection, as well as fecal analysis.
Main Results:
- MTHHF exhibited serum half-lives of 7 and 55 minutes; MTX showed half-lives of 14 and 54 minutes.
- Higher drug concentrations were observed in liver, kidney, and small intestine compared to serum.
- Biliary excretion was 16% for MTHHF and 60% for MTX within 4 hours.
- Urinary excretion over 24 hours was 51% for MTHHF and 41% for MTX.
- Fecal excretion over 24 hours was 21% for MTHHF and 17% for MTX.
Conclusions:
- Both MTHHF and MTX are eliminated via hepatic and renal routes.
- Methotrexate demonstrates a significantly greater extent of enterohepatic circulation compared to 5-methyltetrahydrohomofolate.
- These findings have implications for the dosing and monitoring of these folate analogs in clinical settings.