Pharmacokinetics and central nervous system toxicity of declopramide (3-chloroprocainamide) in rats and mice

Declopramide (3-chloroprocainamide) has been identified in previous studies as a representative of a new class of chemosensitizers. In this study, the toxicity and pharmacokinetics of declopramide have been investigated and c ompared with a structural analog, metoclopramide (MCA). Declopramide has no t induced central nervous system (CNS)-related side effects in rats at dose s up to 200 mg/kg, whereas MCA does at 12.5 mg/kg. In addition, declopramid e did not bind to dopamine D-2 receptors in subcellular preparations at dos es up to 1000 mu M, whereas MCA showed affinity at 1 mu M. Declopramide bou nd with affinity to 5-hydroxytryptamine(3) receptors which are important in controlling vomiting. In contrast to MCA, declopramide has a rapid clearan ce from serum, a lower tissue concentration (about 15-fold lower than MCA) and a lower oral bioavailability (about 6-fold lower than MCA). However, de clopramide was shown in vitro to possess a higher tumor cell absorption rat e. One of the main metabolites of declopramide was identified as N-acetyl d eclopramide. Taken together, these data suggest that the clinical developme nt of declopramide as a sensitizer of radio- and chemotherapies is an impro vement over MCA, because it can be administered in a high dose and is devoi d of CNS side effects. [(C) 1999 Lippincott Williams & Wilkins.]