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