piperidines and 4-piperidinecarboxylic-acid

Carfentanil, a µ-opioid receptor (MOR) agonist with an analgesic potency 10,000 times that of morphine, is extensively metabolized to norcarfentanil (M1), 4-Piperidinecarboxylic acid, 1-(2-hydroxy-2-phenylethyl)-4-[(1-oxopropyl)phenylamino]-, methyl ester (M0 in this article), and other low abundant metabolites in human hepatocytes and liver/lung microsomes. M0 possessed comparable MOR activity to carfentanil, and accounted for approximately 12 % of the total carfentanil metabolite formation in human liver microsomes (HLMs). Little is known about the subsequent elimination of M0. This study investigated its metabolic pathway in HLMs, separation and preliminary identification of metabolites by liquid chromatography-tandem mass spectrometry, and possible involvement of cytochrome P450 enzymes in M0 metabolism with kinetic analysis. M0 produced 9 metabolites via N-dealkylation (M1), oxidation (M3, M6-9), N-dealkylation followed by oxidation (M2 and M4), and glucuronidation (M5). Formation of the major metabolite M1 fitted typical Michaelis-Menten kinetics. Recombinant human CYP3A5 showed the highest activity toward M1 formation followed by CYP3A4 and CYP2C8, while M8 was primarily formed by CYP3A4 followed by CYP2C19 and CYP2C8. These findings reveal the main involvement of CYP3A5 and 3A4 in human hepatic elimination of M0 with a kinetic profile similar to carfentanil which may inform development of treatment protocols for carfentanil exposure.

Topics: Carboxylic Acids; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Esters; Fentanyl; Humans; Kinetics; Microsomes, Liver; Piperidines

A temperature-controlled X-ray powder diffraction experiment, complemented with TGA and DSC analysis, allowed us to follow changes in the molecular conformation and hydrogen-bond patterns of 4-piperidinecarboxylic acid. The presence of three phases is confirmed. Phase 1 represents the monohydrated form of 4-piperidinecarboxylic acid, which exists from room temperature to 359 K, where dehydration occurs. Phase 2 measured at 363 K corresponds to an anhydrous form of the acid. At ca 458 K the onset of a second, more gradual transition is observed, which ends at around 543 K. Phase 3 measured at 543 K is a high-temperature anhydrous form of the acid. The structures of phases 2 and 3 were solved from synchrotron powder diffraction data by simulated annealing using the DASH program and refined by the Rietveld method. The phase changes are accompanied by modification of the hydrogen-bond patterns and of the torsional orientation of the terminal carboxylate group. This group makes a 49 degrees rotation about the C1-C2 bond during the first transition.

Topics: Calorimetry, Differential Scanning; Carboxylic Acids; Hydrogen Bonding; Models, Molecular; Molecular Structure; Phase Transition; Piperidines; Temperature; Thermogravimetry; X-Ray Diffraction