1-[1-(2-Benzo[b]thiopheneyl)cyclohexyl]piperidine hydrochloride (BTCP) yields two active primary metabolites in vivo. Identification and quantification of BTCP primary metabolites in mice plasma, urine, and brain and their affinity for the neuronal dopamine transporter.
1-[1-(2-Benzo[b]thiopheneyl)cyclohexyl]piperidine hydrochloride (BTCP) and cocaine bind to the neuronal dopamine transporter (DAT) to strongly inhibit dopamine (DA) reuptake. Although similar to acute administration, cocaine and BTCP produce sensitization and tolerance, respectively, on chronic administration. We previously found that liver microsomes produced two primary metabolites from BTCP with a high affinity for DAT. Because such metabolites, if produced in vivo, could account for the pharmacological difference with cocaine, it was important to compare BTCP biotransformations in vitro and in vivo. Therefore, we identified and quantified BTCP and primary metabolites in mice urine, plasma, and brain after acute i.p. administration. The low recovery yield suggest that BTCP might behave like its close analogue, phencyclidine, with long-term storage of metabolites. Two active metabolites found in vitro were found in mice brain with estimated half-life values similar to that of BTCP ( approximately 0.3 h). Although respective brain concentrations were 20 and 40 times lower than that of BTCP, their potency to displace in vivo [3H]BTCP bound to the DAT was 50 and 10 times higher, respectively, than that of BTCP. They could, therefore, contribute to the inhibition of DA transport and play an important role in BTCP pharmacology. They could also explain the differences between BTCP and cocaine on repeated administration.
Deleuze-Masquefa
C
C
CRBM, CNRS-UPR 1086 and INSERM U 336, Ecole Nationale Supérieure de Chimie, 8, rue de l'Ecole Normale, 34296, Montpellier, France.
Michaud-Dutreilh
M
M
Vignon
J
J
Kamenka
J M
JM
D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002352:Carrier Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D050483:Dopamine Plasma Membrane Transport Proteins; D008401:Gas Chromatography-Mass Spectrometry; D007274:Injections, Intraperitoneal; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000378:metabolism*; D010622:Phencyclidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000652:urine; D011485:Protein Binding; D013056:Spectrophotometry, Ultraviolet; D014316:Tritium
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493215:Slc6a3 protein, mouse; D014316:Tritium; C056415:1-(1-(2-benzo(b)thienyl)cyclohexyl)piperidine; D010622:Phencyclidine