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

Abstract

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 compared with a structural analog, metoclopramide (MCA). Declopramide has not induced central nervous system (CNS)-related side effects in rats at doses up to 200 mg/kg, whereas MCA does at 12.5 mg/kg. In addition, declopramide did not bind to dopamine D2 receptors in subcellular preparations at doses up to 100 microM, whereas MCA showed affinity at 1 microM. Declopramide bound with affinity to 5-hydroxytryptamine3 receptors which are important in controlling vomiting. In contrast to MCA, declopramide has a rapid clearance from serum, a lower tissue concentration (about 15-fold lower than MCA) and a lower oral bioavailability (about 6-fold lower than MCA). However, declopramide was shown in vitro to possess a higher tumor cell absorption rate. One of the main metabolites of declopramide was identified as N-acetyl declopramide. Taken together, these data suggest that the clinical development of declopramide as a sensitizer of radio- and chemotherapies is an improvement over MCA, because it can be administered in a high dose and is devoid of CNS side effects.

• Authors: J Hua, R W Pero, R Kane
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 10 Issue 1 Pg. 79-88 (Jan 1999) ISSN: 0959-4973 [Print] England
• PMID: 10194550 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiemetics
• Dopamine Antagonists
• Receptors, Dopamine D2
• Receptors, Serotonin
• Receptors, Serotonin, 5-HT3
• declopramide
• Procainamide
• Metoclopramide

Topics

• Administration, Oral
• Animals
• Antiemetics (pharmacokinetics, toxicity)
• Biological Availability
• Central Nervous System (drug effects)
• Dopamine Antagonists (pharmacokinetics, toxicity)
• Dose-Response Relationship, Drug
• Female
• Metoclopramide (pharmacokinetics, toxicity)
• Mice
• Mice, SCID
• Procainamide (analogs & derivatives, metabolism, pharmacokinetics, toxicity)
• Rats
• Rats, Wistar
• Receptors, Dopamine D2 (metabolism)
• Receptors, Serotonin (metabolism)
• Receptors, Serotonin, 5-HT3
• Sleep Stages (drug effects)
• Tissue Distribution