detected by mass spectrometry indicate that the phenyl group on the imidazole ring of SCH 66712 is one site of oxidation by CYP2D6 and could lead to methylene quinone formation. Three other metabolites were also observed. For understanding the metabolic pathway that leads to CYP2D6 inactivation, metabolism studies with CYP2C9 and CYP2C19 were performed because neither of these enzymes is significantly inhibited by SCH 66712. The metabolites formed by CYP2C9 and CYP2C19 are the same as those seen with CYP2D6, although in different abundance. Modeling studies with CYP2D6 revealed potential roles of various active site residues in the oxidation of SCH 66712 and inactivation of CYP2D6 and showed that the phenyl group of SCH 66712 is positioned at 2.2 Å from the heme iron.

Human cytochrome P450 2D6 (CYP2D6) is involved in metabolism of approximately 25% of pharmaceutical drugs. Inactivation of CYP2D6 can lead to adverse drug interactions. Four inactivators of CYP2D6 have previously been identified: 5-Fluoro-2-[4-[(2-phenyl-1H-imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine (SCH66712), (1-[(2-ethyl-4-methyl-1H(-EMTPP-imidazol-5-yl)-methyl]-4-[4-(trifluoromethyl)-2-pyridinyl]piperazine (EMTPP), paroxetine, and 3,4-methylenedioxymethamphetamine (MDMA). All four contain planar, aromatic groups as well as basic nitrogens common to CYP2D6 substrates. SCH66712 and EMTPP also contain piperazine groups and substituted imidazole rings that are common in pharmaceutical agents, though neither of these compounds is clinically relevant. Paroxetine and MDMA contain methylenedioxyphenyls. SCH66712 and EMTPP are both known protein adductors while paroxetine and MDMA are probable heme modifiers. The current study shows that each inactivator displays Type I binding with Ks values that vary by 2-orders of magnitude with lower Ks values associated with greater inactivation. Comparison of KI, kinact, and partition ratio values shows SCH66712 is the most potent inactivator. Molecular modeling experiments using AutoDock identify Phe120 as a key interaction for all four inactivators with face-to-face and edge-to-face pi interactions apparent. Distance between the ligand and heme iron correlates with potency of inhibition. Ligand conformations were scored according to their binding energies as calculated by AutoDock and correlation was observed between molecular models and Ks values.

There are four known and confirmed mechanism‐based inactivators of human cytochrome P450 2D6: SCH 66712, EMTPP, paroxetine, and 3,4‐methylenedioxymethamphetamine (MDMA). SCH 66712 and EMTPP contain piperazine groups and substituted imidazole rings; previous studies with each have indicated that inactivation occurs by reaction with the substituents of the imidazole ring. Paroxetine and MDMA contain methylenedioxyphenyls; the moiety responsible for inactivation is unknown. The current study shows that each inactivator displays Type I binding with Ks values that vary by 2‐orders of magnitude. Comparison of Ki and kinact and partition ratio values shows Schering 66712 is the most potent inactivator. Molecular modeling experiments using AutoDock identify Phe120 as a key interaction for all four inactivators with face‐to‐face and edge‐to‐edge pi interactions apparent. Also, modeling suggests Thr309 could be a potential site for inactivation. Ligand conformations were scored according to their binding energies as calculated by AutoDock and correlation was observed between molecular models and Ks values. (Support: NIH 1R15‐GM086767‐01 & ‐01S1; HHMI [52006304] to Kalamazoo College).

Background: The prevalence of abdominal aortic aneurysm (AAA) is 1-2 percent in the general population, and is as high as 6 percent in groups with risk factors. Objectives: The aim of this study was to determine the prevalence of AAA amongst high-risk cardiac patients in the emergency department (ED). Methods: A prospective study was conducted to evaluate the prevalence of AAA in a high-risk population presenting to the ED. Inclusion criteria included male gender, Caucasian race, age over 50 years, history of smoking, and presentation to the ED with chest pain requiring admission. Patients enrolled in the study were screened for AAA by ultrasound (US) scan. Study subjects were excluded if there was inadequate imaging. Results: One hundred and nine patients were recruited into the study. Nineteen patients were excluded by the ED US Director secondary to inadequate imaging. Of the remaining 90 patients, eight patients were found to have AAA (n = 8; 8.9%; CI 3.9 - 16.8%). Of the eight patients with an AAA, four had diagnosed cardiovascular disease during their hospital admission. There was no statistically significant difference in secondary risk factors such as hypertension, diabetes, dyslipidemia or previous history of coronary artery disease between those with AAA and those without AAA. Conclusions: This study found that in a single ED, the prevalence of AAA in high-risk cardiac patients admitted to rule out acute coronary syndrome who could be adequately visualized with ultrasound was over 8 percent. With such a high prevalence, this population could be a potential screening group.

Schering 66712 (5‐fluoro‐2‐[4‐[(2‐phenyl‐1H‐imidazol5‐yl)methyl]‐1‐piperzainyl]pyrimidine) is a mechanism‐based inactivator of human cytochrome P450 2D6 (P450 2D6) that displays Type I binding with KS of 0.39 ± 0.10 μM. The partition ratio is approximately 300. Inactivation was not prevented by addition of an exogenous nucleophiles including potassium cyanide. Within 15 minutes of incubation with Schering 66712 and NADPH, ~100% of P450 2D6 activity was lost with ~40% loss in ability to binding CO. These findings support inactivation primarily by adduction of protein. ESI‐LC‐MS analysis of whole protein also indicates the presence of a protein adduct. Modeling of Schering 66712 in the active site of P450 2D6 suggests interaction between the phenyl group of Schering 66712 and the heme iron. (Supported by: NIH GM086767‐01 and RGM086767Z, a grant from the Howard Hughes Medical Institute to Kalamazoo College, and the Hutchcroft Fund of Kalamazoo College).