Supplemental Information for: METABOLISM OF RAMELTEON IN HUMAN LIVER MICROSOMES AND CORRELATION WITH THE EFFECT OF FLUVOXAMINE ON RAMELTEON PHARMACOKINETICS by R. Scott Obach and Tim F. Ryder Drug Metabolism and Disposition Figures S1a-S8d: Mass spectral and NMR spectral data for ramelteon metabolites

MS1 MS2 dau 260 MS3 dau 204 Figure S-1a; Ramelteon

Ramelteon NMR Assignments COSY: Black Arrows HMBC: Red Arrows Figure S-1b

1 H NMR Spectrum of Ramelteon Figure S-1c

COSY NMR Spectrum of Ramelteon Figure S-1d

HSQC NMR Spectrum of Ramelteon Figure S-1e

HMBC NMR Spectrum of Ramelteon Figure S-1f

MS1 MS2 dau 276 MS3 dau 258 MS4 dau 159 Figure S-2a; Metabolite A

COSY: Black Arrows Figure S-2b; Metabolite A

1 H NMR Spectrum Figure S-2c; Metabolite A

COSY NMR Spectrum Figure S-2d; Metabolite A

HSQC NMR Spectrum Figure S-2e; Metabolite A

Figure S-3a; Metabolite B MS1 MS2 dau 258 MS3 dau 202

COSY: Black Arrows Figure S-3b; Metabolite B

1 H NMR Spectrum Figure S-3c; Metabolite B

1 H NMR Spectrum Showing Diastereomeric Mixture Hydroxyl Proton 1 Hydroxyl Proton 2 Extra coupling of the aromatic doublets Methine Figure S-3d; Metabolite B

COSY NMR Spectrum Figure S-3e; Metabolite B

HSQC NMR Spectrum Figure S-3f; Metabolite B

Figure S-4a; Metabolite C MS1 MS2 dau 258 MS3 dau 202

COSY: Black Arrows Figure S-4b; Metabolite C

1 H NMR Spectrum Figure S-4c; Metabolite C

COSY NMR Spectrum Figure S-4d; Metabolite C

HSQC NMR Spectrum Figure S-4e; Metabolite C

Figure S-5a; Metabolite D MS1 MS2 dau 276 MS3 dau 185

COSY: Black Arrows Figure S-5b; Metabolite D

1 H NMR Spectrum Figure S-5c; Metabolite D

1 H NMR Spectrum Showing the Ratio of Regioisomers New Aromatic Singlet Together integrate to about 1 Figure S-5d; Metabolite D

COSY NMR Spectrum Figure S-5e; Metabolite D

Figure S-6a; Metabolites E and F MS1 MS2 dau 258 MS3 dau 159

COSY: Black Arrows Figure S-6b; Metabolites E and F

1 H NMR Spectrum Figure S-6c; Metabolites E and F

1 H NMR Spectrum Shows Diastereomeric Mixture Hydroxyl Proton 1 Methine 1 Hydroxyl Proton 2 Methine 2 Figure S-6d; Metabolites E and F

COSY NMR Spectrum Figure S-6f; Metabolites E and F

Figure S-7a; Metabolite G MS1 MS2 dau 258 MS3 dau 185

COSY: Black Arrows Figure S-7b; Metabolite G

1 H NMR Spectrum Figure S-7c; Metabolite G

COSY NMR Spectrum Figure S-7d; Metabolite G

HSQC NMR Spectrum Figure S-7e; Metabolite G No Methine

Figure S-8a; Metabolite H MS1 MS2 dau 274 MS3 dau 256

COSY: Black Arrows Figure S-8b; Metabolite H

1 H NMR Spectrum Figure S-8c; Metabolite H

COSY NMR Spectrum Figure S-8d; Metabolite H