Metabolism and disposition of EXP631--a novel antidepressant analgesic.
EXP631, 4-(3-thienyl)-alpha, alpha,1-trimethyl-4-piperidine-methanol hemi-fumarate salt (I), is a centrally acting non-opioid analgesic compound with monoamine uptake blocking properties. EXP631 has analgesic effects in several animal models. It is intended to be used for the treatment of moderate to moderately severe acute and chronic pain. To characterize the disposition of EXP631, the plasma levels of EXP631 were determined in rats and dogs after single intravenous and oral doses. In rats, EXP631 was rapidly absorbed following a single oral solution dose of 5-20 mg kg-1 with maximum plasma levels detected within 1.2 h post dose. The absorption was complete with an oral bioavailability of 92-131%. The pharmacokinetics was dose independent as measured by either Cmax or AUC values. In fasted dogs, EXP631 was absorbed rapidly and well (F = 81%) from an oral solution with the maximum concentration detected at 20 min post dose. In fed dogs, the absorption from capsules was slower (1.38 h) compared to the solution, but the absorption was complete (F = 115%). An N-desmethyl metabolite (II) was found in both rat and dog plasma samples. The structure was confirmed by mass spectroscopy, nuclear magnetic resonance spectroscopy and comparative chromatographic retention times. The metabolite is inactive as an analgesic.
Wong
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Du Pont Merck Pharmaceutical Company, Drug Metabolism and Pharmacokinetics Section, Stine-Haskell Research Center, Newark, DE 19714.
Burcham
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DL
Huang
S M
SM
Quon
C Y
CY
D000284:Administration, Oral; D000700:Analgesics / Q000097:blood* / Q000493:pharmacokinetics*; D000818:Animals; D000928:Antidepressive Agents / Q000097:blood* / Q000493:pharmacokinetics*; D004285:Dogs; D007275:Injections, Intravenous; D008297:Male; D010880:Piperidines; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes
D000700:Analgesics; D000928:Antidepressive Agents; D010880:Piperidines; D013876:Thiophenes; C084030:EXP 631