Metabolism of a 5HT Antagonist, 2-Methyl-1-(Phenylsulfonyl)-4-(Piperazin-1-yl)-1H-Benzo[d]imidazole (SAM-760): Impact of Sulfonamide Metabolism on Diminution of a Ketoconazole-Mediated Clinical Drug-Drug Interaction.
Aarti Sawant-Basak, R Scott Obach, Angela Doran, Peter Lockwood, Klaas Schildknegt, Hongying Gao, Jessica Mancuso, Susanna Tse, Thomas A Comery
Author Information
Aarti Sawant-Basak: Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Cambridge, Massachusetts (A.S.-B.); Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Groton, Connecticut (R.S.O., A.D., H.G., S.T.); Pfizer Global Product Development, Groton, Connecticut (P.L.); Pfizer Worldwide Research and Development Pharmaceutical Sciences Chemical Research and Development, Groton, Connecticut (K.S.); Pfizer Worldwide Research and Development, Research Statistics, Cambridge, Massachusetts (J.M.); and Pfizer Neuroscience and Pain Research Unit, Worldwide Research and Development, Cambridge, Massachusetts (T.A.C.) aarti.sawant@pfizer.com.
R Scott Obach: Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Cambridge, Massachusetts (A.S.-B.); Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Groton, Connecticut (R.S.O., A.D., H.G., S.T.); Pfizer Global Product Development, Groton, Connecticut (P.L.); Pfizer Worldwide Research and Development Pharmaceutical Sciences Chemical Research and Development, Groton, Connecticut (K.S.); Pfizer Worldwide Research and Development, Research Statistics, Cambridge, Massachusetts (J.M.); and Pfizer Neuroscience and Pain Research Unit, Worldwide Research and Development, Cambridge, Massachusetts (T.A.C.).
Angela Doran: Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Cambridge, Massachusetts (A.S.-B.); Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Groton, Connecticut (R.S.O., A.D., H.G., S.T.); Pfizer Global Product Development, Groton, Connecticut (P.L.); Pfizer Worldwide Research and Development Pharmaceutical Sciences Chemical Research and Development, Groton, Connecticut (K.S.); Pfizer Worldwide Research and Development, Research Statistics, Cambridge, Massachusetts (J.M.); and Pfizer Neuroscience and Pain Research Unit, Worldwide Research and Development, Cambridge, Massachusetts (T.A.C.).
Peter Lockwood: Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Cambridge, Massachusetts (A.S.-B.); Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Groton, Connecticut (R.S.O., A.D., H.G., S.T.); Pfizer Global Product Development, Groton, Connecticut (P.L.); Pfizer Worldwide Research and Development Pharmaceutical Sciences Chemical Research and Development, Groton, Connecticut (K.S.); Pfizer Worldwide Research and Development, Research Statistics, Cambridge, Massachusetts (J.M.); and Pfizer Neuroscience and Pain Research Unit, Worldwide Research and Development, Cambridge, Massachusetts (T.A.C.).
Klaas Schildknegt: Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Cambridge, Massachusetts (A.S.-B.); Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Groton, Connecticut (R.S.O., A.D., H.G., S.T.); Pfizer Global Product Development, Groton, Connecticut (P.L.); Pfizer Worldwide Research and Development Pharmaceutical Sciences Chemical Research and Development, Groton, Connecticut (K.S.); Pfizer Worldwide Research and Development, Research Statistics, Cambridge, Massachusetts (J.M.); and Pfizer Neuroscience and Pain Research Unit, Worldwide Research and Development, Cambridge, Massachusetts (T.A.C.).
Hongying Gao: Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Cambridge, Massachusetts (A.S.-B.); Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Groton, Connecticut (R.S.O., A.D., H.G., S.T.); Pfizer Global Product Development, Groton, Connecticut (P.L.); Pfizer Worldwide Research and Development Pharmaceutical Sciences Chemical Research and Development, Groton, Connecticut (K.S.); Pfizer Worldwide Research and Development, Research Statistics, Cambridge, Massachusetts (J.M.); and Pfizer Neuroscience and Pain Research Unit, Worldwide Research and Development, Cambridge, Massachusetts (T.A.C.).
Jessica Mancuso: Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Cambridge, Massachusetts (A.S.-B.); Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Groton, Connecticut (R.S.O., A.D., H.G., S.T.); Pfizer Global Product Development, Groton, Connecticut (P.L.); Pfizer Worldwide Research and Development Pharmaceutical Sciences Chemical Research and Development, Groton, Connecticut (K.S.); Pfizer Worldwide Research and Development, Research Statistics, Cambridge, Massachusetts (J.M.); and Pfizer Neuroscience and Pain Research Unit, Worldwide Research and Development, Cambridge, Massachusetts (T.A.C.).
Susanna Tse: Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Cambridge, Massachusetts (A.S.-B.); Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Groton, Connecticut (R.S.O., A.D., H.G., S.T.); Pfizer Global Product Development, Groton, Connecticut (P.L.); Pfizer Worldwide Research and Development Pharmaceutical Sciences Chemical Research and Development, Groton, Connecticut (K.S.); Pfizer Worldwide Research and Development, Research Statistics, Cambridge, Massachusetts (J.M.); and Pfizer Neuroscience and Pain Research Unit, Worldwide Research and Development, Cambridge, Massachusetts (T.A.C.).
Thomas A Comery: Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Cambridge, Massachusetts (A.S.-B.); Pfizer Worldwide Research and Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Groton, Connecticut (R.S.O., A.D., H.G., S.T.); Pfizer Global Product Development, Groton, Connecticut (P.L.); Pfizer Worldwide Research and Development Pharmaceutical Sciences Chemical Research and Development, Groton, Connecticut (K.S.); Pfizer Worldwide Research and Development, Research Statistics, Cambridge, Massachusetts (J.M.); and Pfizer Neuroscience and Pain Research Unit, Worldwide Research and Development, Cambridge, Massachusetts (T.A.C.).
SAM-760 [(2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole)], a 5HT antagonist, was investigated in humans for the treatment of Alzheimer's disease. In liver microsomes and recombinant cytochrome P450 (P450) isozymes, SAM-760 was predominantly metabolized by CYP3A (∼85%). Based on these observations and an expectation of a 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed. In the presence of ketoconazole, the mean and area under the plasma concentration-time curve from time zero extrapolated to infinite time values of SAM-760 showed only a modest increase by 30% and 38%, respectively. In vitro investigation of this unexpectedly low interaction was undertaken using [C]SAM-760. Radiometric profiling in human hepatocytes confirmed all oxidative metabolites previously observed with unlabeled SAM-760; however, the predominant radiometric peak was an unexpected polar metabolite that was insensitive to the pan-P450 inhibitor 1-aminobenzotriazole. In human hepatocytes, radiometric integration attributed 43% of the total metabolism of SAM-760 to this non-P450 pathway. Using an authentic standard, this predominant metabolite was confirmed as benzenesulfinic acid. Additional investigation revealed that the benzenesulfinic acid metabolite may be a novel, nonenzymatic, thiol-mediated reductive cleavage of an aryl sulfonamide group of SAM-760. We also determined the relative contribution of P450 to the metabolism of SAM-760 in human hepatocytes by following the rate of formation of oxidative metabolites in the presence and absence of P450 isoform-specific inhibitors. The P450-mediated oxidative metabolism of SAM-760 was still primarily attributed to CYP3A (33%), with minor contributions from P450 isoforms CYP2C19 and CYP2D6. Thus, the disposition of [C]SAM-760 in human hepatocytes via novel sulfonamide metabolism and CYP3A verified the lower than expected clinical DDI when SAM-760 was coadministered with ketoconazole.
