The processing of the selective M1 agonist CDD-0102-J by human hepatic drug metabolizing enzymes.
The in vitro metabolism of the selective M1 muscarinic agonist CDD-0102-J was evaluated in heterologous systems expressing individual human cytochrome P-450 (CYP) isoenzymes and also in suspensions of cryopreserved human hepatocytes. In all experiments, the metabolism of CDD-0102-J was characterized based on its rate of disappearance using an HPLC assay since no metabolites have as yet been characterized. The human CYP isoenzymes used were CYP1A2, 2A6, 2B6, 2C8, 2C19, 2D6, and 3A4. Measurable decreases in CDD-0102-J concentrations over time were detectable only in systems containing either CYP2D6 or CYP2C8, although the unbound in vitro clearance was more than 20 times larger for CYP2D6 (7.6 mL h(-1) nmol(-1)) than for CYP2C8 (0.35 mL h(-1) nmol(-1)). When scaled to in vivo hepatic clearance based on just CYP2D6 and CYP2C8, the projected hepatic clearance for CDD-0102-J was 7.7 L h(-1), which corresponded closely with the hepatic clearance of 8.4 L h(-1) scaled from experiments using cryopreserved human hepatocytes.
Bachmann
Kenneth
K
Department of Pharmacology, The University of Toledo, Toledo, Ohio 43606, USA. kbachma@utnet.utoledo.edu
Telang
Urvi
U
Byers
James
J
Hoss
Wayne
W
D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D018721:Muscarinic Agonists / Q000493:pharmacokinetics*; D010069:Oxadiazoles / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D043643:Receptor, Muscarinic M1 / Q000819:agonists*
C506571:CDD-0102-J; D007527:Isoenzymes; D018721:Muscarinic Agonists; D010069:Oxadiazoles; D011743:Pyrimidines; D043643:Receptor, Muscarinic M1; D003577:Cytochrome P-450 Enzyme System