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Clearance studies of methotrexate and 7-hydroxy-methotrexate in rabbits after multiple-dose infusion
Abstract:
The concentration-dependent clearance of methotrexate (MTX) and its metabolite, 7-hydroxy-methotrexate (7-OH-MTX), was demonstrated in 5 rabbits using 7 infusion rates (10.5-323 mg/hr). Mean total body clearance (from 34.3 to 13.1 ml/min) and mean renal clearance (from 25.6 to 7.6 ml/min) of MTX were found to decrease with increasing steady-state plasma concentrations (from 5.1 to 412 micrograms/ml), whereas nonrenal clearances remained relatively constant. An essentially steady-state plasma level of 7-OH-MTX was achieved during each MTX infusion, and its renal clearance also decreased (from 37.3 to 6.5 ml/min) with increasing metabolite levels (from 1.8 to 293 micrograms/ml). Saturable renal tubular secretion appeared operative for both drug and metabolite since their renal clearance (based on the free drug) to inulin clearance ratios were much greater than unity and the ratios were markedly reduced in 2 rabbits after probenecid treatment. Plasma protein binding of MTX (56%) and 7-OH-MTX (49%) were independent of concentrations between 0.1 and 300 micrograms/ml. Negligible MTX metabolism was found in rabbit kidney homogenates, thus validating renal clearance measurement in the present study.
Insights
Methotrexate (MTX) clearance and its metabolite 7-hydroxy-methotrexate (7-OH-MTX) decrease with increasing plasma concentrations in rabbits, indicating saturable renal tubular secretion for both. This impacts drug elimination dynamics.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Renal Physiology
- Toxicology
Background:
- Methotrexate (MTX) is a crucial chemotherapy agent.
- Understanding MTX and its metabolite 7-hydroxy-methotrexate (7-OH-MTX) clearance is vital for optimizing dosing and minimizing toxicity.
- Renal function significantly influences MTX elimination.
Purpose of the Study:
- To investigate the concentration-dependent clearance of MTX and 7-OH-MTX in rabbits.
- To elucidate the role of renal tubular secretion in MTX and 7-OH-MTX elimination.
- To assess the impact of probenecid on MTX and 7-OH-MTX renal clearance.
Main Methods:
- Administered MTX via intravenous infusion at varying rates (10.5-323 mg/hr) to 5 rabbits.
- Measured plasma concentrations of MTX and 7-OH-MTX over time.
- Determined total body, renal, and nonrenal clearance rates.
- Assessed renal clearance using inulin clearance ratios and evaluated the effect of probenecid.
Main Results:
- Concentration-dependent decrease in MTX total body clearance (34.3 to 13.1 ml/min) and renal clearance (25.6 to 7.6 ml/min) with increasing plasma concentrations (5.1 to 412 µg/ml).
- Saturable renal tubular secretion was evident for both MTX and 7-OH-MTX, indicated by high renal to inulin clearance ratios, significantly reduced by probenecid.
- Plasma protein binding for MTX (56%) and 7-OH-MTX (49%) remained constant across tested concentrations.
Conclusions:
- Renal tubular secretion is a saturable pathway for MTX and 7-OH-MTX elimination in rabbits.
- MTX clearance is concentration-dependent, primarily due to saturable renal mechanisms.
- These findings highlight the importance of renal function in MTX pharmacokinetics and suggest potential for drug interactions affecting its elimination.