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Urinary excretion of MPTP and its primary metabolites in mice
Y S Lau1, J M Crampton, J A Wilson
1Department of Pharmacology, Creighton University, Omaha, NE 68178.
Abstract:
Mice were injected with single doses of MPTP (15 mg/kg, s.c.) containing one microCi of [3H]methyl-MPTP. Approximately 42% of the total injected [3H] was detected in the urine within 3 hours after drug administration. The early urine samples were analyzed using high pressure liquid chromatography. MPTP N-oxide was identified as a major metabolite, with trace amounts of MPP+ and MPTP also detected. The urinary volume and excretion of MPTP metabolites were inhibited by pretreating the animals with probenecid (250 mg/kg, i.p.). These results indicate that large amounts of injected MPTP are rapidly metabolized in the periphery by liver enzymes to form MPTP N-oxide.
Insights
MPTP is rapidly metabolized in the periphery into MPTP N-oxide, primarily by liver enzymes. Urinary excretion of these metabolites is reduced by probenecid.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin that causes Parkinsonism.
- Understanding MPTP metabolism is crucial for neuroprotection research.
Purpose of the Study:
- To investigate the peripheral metabolism and urinary excretion of MPTP in mice.
- To identify the major metabolites of MPTP and factors influencing their excretion.
Main Methods:
- Mice were injected with radiolabeled MPTP ([3H]methyl-MPTP).
- Urine samples were collected and analyzed using high-pressure liquid chromatography (HPLC).
- The effect of probenecid on metabolite excretion was assessed.
Main Results:
- Approximately 42% of injected [3H] was recovered in urine within 3 hours.
- MPTP N-oxide was identified as the major urinary metabolite.
- Trace amounts of MPP+ and MPTP were also detected.
- Probenecid significantly inhibited urinary volume and MPTP metabolite excretion.
Conclusions:
- MPTP is rapidly metabolized in the periphery, mainly by liver enzymes, to MPTP N-oxide.
- Urinary excretion of MPTP metabolites is influenced by renal transport mechanisms, as suggested by probenecid inhibition.