Abstract 3167: Comparison of the pharmacokinetics of phenanthrene in smokers after oral ingestion or inhalation through cigarettes for potential lung cancer susceptibility assessment

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Polycyclic aromatic hydrocarbons (PAHs) are believed to be among the critical causative agents for lung cancer in smokers. PAHs require metabolic activation to elicit carcinogenic effects. Our hypothesis is that individuals who metabolically activate PAH more effectively will be at higher risk for lung cancer. Many studies investigated PAHs’ metabolism in human tissue in vitro or in animals. However, direct pharmacokinetics data in human are lacking. There are to our knowledge no data on human PAH pharmacokinetics after exposure by inhalation, from a cigarette or from any other source. We used a unique approach employing a stable isotope labeled phenanthrene (Phe), the simplest PAH with a bay region, a feature closely associated with PAH carcinogenicity. Deuterated Phe ([D10]Phe) was administered to 15 subjects in a within-subject crossover and randomized clinical study, either by oral administration or by incorporation into cigarettes. Serial blood samples were taken at baseline and over 24 h after [D10]Phe administration. Urine was collected during 8 intervals over 48 h after dosing. Deuterated r,1-t-2,3, c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene ([D10]PheT), the metabolic activation end product, in blood and urine samples, was analyzed by GC-MS/MS. Two pharmacokinetic (PK) methods including plasma AUCs and the total amount of [D10]PheT excreted in the urine were used to determine the exposure to [D10]PheT after the two routes of administration. Levels of [D10]PheT in plasma of all subjects were maximal 15-30 min after smoking a cigarette containing [D10]Phe, and decreased thereafter, which suggested that there was significant pulmonary “first-pass” formation of [D10]PheT. Maximum levels of [D10]PheT in plasma occurred between 30 to 150 min after oral ingestion. The relative exposure to [D10]PheT from oral dosing vs smoking was 0.92 ± 0.24 and 0.83 ± 0.28, based on the ratio of plasma AUCs and the ratio of the amount of PheT excreted in the urine, respectively. There was no statistically significant difference in [D10]PheT after two administration routes. There was large inter-individual variation in the capacity of generating [D10]PheT. The AUC ranged from 6560 to 92200 fmol-min/ml with a terminal elimination half-life of 290-681 min. Total urinary excretion ranged from 0.72% to 20.51% of initial dosing. This study showed for the first time that the formation of PAH diol epoxides, as monitored by [D10]PheT, occurred with remarkable rapidity in all subjects after smoking. Oral dosing of [D10]Phe with subsequent urine collections will adequately reflect individual capacity to metabolically activate [D10]Phe. The results demonstrate that this approach is feasible for potentially identifying those individuals who have particularly high capacity to metabolic activate bay region-PAH. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3167. doi:10.1158/1538-7445.AM2011-3167