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 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.
Hua
J
J
Department of Cell and Molecular Biology, University of Lund, Sweden. jianyi.hua@wblab.lu.se
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D000284:Administration, Oral; D000818:Animals; D000932:Antiemetics / Q000493:pharmacokinetics / Q000633:toxicity; D001682:Biological Availability; D002490:Central Nervous System / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D008787:Metoclopramide / Q000493:pharmacokinetics / Q000633:toxicity; D051379:Mice; D016513:Mice, SCID; D011342:Procainamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3; D012894:Sleep Stages / Q000187:drug effects; D014018:Tissue Distribution
D000932:Antiemetics; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; C072799:declopramide; D011342:Procainamide; D008787:Metoclopramide