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Neurotoxicity risk assessment of MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) as a synthetic impurity of drugs

Institute of Toxicology, Merck KGaA, D-64271 Darmstadt, Germany

John Caldwell

Division of Biomedical Sciences, Imperial College School of Medicine, London W2 1PG, UK

Andreas Hofmann

Institute of Toxicology, Merck KGaA, D-64271 Darmstadt, Germany

Peter Tempel

Institute of Toxicology, Merck KGaA, D-64271 Darmstadt, Germany

Guenter Weisse

Institute of Toxicology, Merck KGaA, D-64271 Darmstadt, Germany

1-Methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) induces symptoms indistinguishable from those of Parkinson's disease. It selectively destroys dopaminergic neurons in the substantia nigra and the globus pallidus. Death of these same neurons is apparently the cause of idiopathic Parkinson's disease. As phenyl-1,2,3,6 tetrahydropyridine is a commonly encountered subunit in heterocyclic drugs and because MPTP was found as a minor impurity in early batches of a candidate drug at Merck KGaA, it may be assumed that MPTP will also be present as an as yet undiscovered minor impurity in various existing drugs. A neurotoxicity risk assessment on MPTP has been conducted to define the risk of MPTP as an impurity in drugs that are used orally. This risk assessment has shown that compounds containing less than 5.0 p.p.m. MPTP administered orally will not cause a neurotoxicological health risk to patients treated with such a drug.

Key Words: risk assessment • N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine • impurity • drugs • pesticides • neurotoxicity

Human & Experimental Toxicology, Vol. 17, No. 5, 283-293 (1998)
DOI: 10.1177/096032719801700514


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