RT Journal Article SR Electronic T1 Evaluation of Accelerator Mass Spectrometry in a Human Mass Balance and Pharmacokinetic Study–Experience with14C-labeled (R)-6-[Amino(4- chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1- methyl-2(1H)-quinolinone (R115777), a Farnesyl Transferase Inhibitor JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 823 OP 830 DO 10.1124/dmd.30.7.823 VO 30 IS 7 A1 R. C. Garner A1 I. Goris A1 A. A. E. Laenen A1 E. Vanhoutte A1 W. Meuldermans A1 S. Gregory A1 J. V. Garner A1 D. Leong A1 M. Whattam A1 A. Calam A1 C. A. W. Snel YR 2002 UL http://dmd.aspetjournals.org/content/30/7/823.abstract AB Accelerator mass spectrometry (AMS) has been used in a human mass balance and metabolism study to analyze samples taken from four healthy male adult subjects administered nanoCurie doses of the farnesyl transferase inhibitor 14C-labeled (R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone ([14C]R115777). Plasma, urine, and feces samples were collected at fixed timepoints after oral administration of 50 mg [14C]R115777 (25.4 Bq/mg or 687 pCi/mg i.e., equivalent to 76.257 × 103 dpm) per subject. AMS analysis showed that drug-related 14C was present in the plasma samples with Cmax values ranging from 1.6055 to 2.9074 dpm/ml (1.0525–1.9047 μg/ml) attmax = 2 to 3 h. TheCmax values for acetonitrile extracts of plasma samples ranged from 0.3724 to 0.7490 dpm/ml in the four male subjects. Drug-related 14C was eliminated from the body both in the urine and the feces, with a mean total recovery of 79.8 ± 12.9% in the feces and 13.7 ± 6.2% in the urine. The majority of drug-related radioactivity in urine and feces was excreted within the first 48 h. High-performance liquid chromatography (HPLC)-AMS profiles were generated from radioactive parent drug plus metabolites from pooled diluted urine, plasma, and methanolic feces extracts and matched to retention times of synthetic reference substances, postulated as metabolites. All HPLC separations used no more than 5 dpm injected on-column. The radioactive metabolite profiles obtained compared well with those obtained using liquid chromatography/tandem mass spectometry. This study demonstrates the use of AMS in a human phase I study in which the administered radioactive dose was at least 1000-fold lower than that used for conventional radioactive studies. The American Society for Pharmacology and Experimental Therapeutics