Cell membrane lytic action of metoclopramide and its relation to tardive dyskinesia

The long-term use of many antipsychotic medications carries a risk of tardive dyskinesia in a small proportion of patients. Although metoclopramide is an antipsychotic at high doses, this drug is more commonly used at low daily doses to accelerate stomach movement of food. Because prolonged use of metoclopramide has also been associated with tardive dyskinesia, this drug is convenient to study to examine the possible basis of tardive dyskinesia. Previous work proposed that antipsychotics accumulated in the melanin granules of the human substantia nigra, ultimately building up to high concentrations that could disrupt cell membranes of nigral neurons. While previous work demonstrated the accumulation of metoclopramide in postmortem human nigral tissue, it remained to be tested whether high concentrations of metoclopramide would actually disrupt cell membranes. Therefore, the present work examined whether metoclopramide could disrupt cell membranes, using human erythrocytes directly exposed to various concentrations of metoclopramide in vitro. It was found that metoclopramide caused disruption of the red cells starting at a threshold of 1 mM, which would result in ~280 μmoles of metoclopramide per kilogram of dry red cell membranes. However, the nonspecific adsorption of metoclopramide to human substantia nigra is ~23 μmol/kg of dry solids (measured at the clinical spinal fluid concentration of metoclopramide). Therefore, the membrane-lytic concentration of metoclopramide is only about 12 times higher than that after a single exposure of the drug to the nigral tissue. Hence, metoclopramide accumulation in the substantia nigra over a matter of months may lead to nigral neuron damage.