title: Acute intravenous and inhalation pharmacokinetics of 2,4-pentanedione in the Fischer 344 rat.
abstract: 2,4-Pentanedione (2,4-PD; CAS No. 123-54-6), an industrial chemical, was investigated for its comparative pharmacokinetics in male Fischer 344 rats by a single intravenous (i.v.) injection of (4.3, 43, 148.5, and 430 mg/kg), or a 6-hr nose-only inhalation exposure (400 ppm) to 14C-2,4-PD. For the i.v. route, the plasma concentration of 14C-2,4-PD-derived radioactivity declined in a biexponential fashion. The overall form of the 14C plasma concentration-time curves and derived pharmacokinetic parameters indicated that dose-linear kinetics occurred in the i.v. dose range 4.3-148.5 mg/kg, but not with 430 mg/kg. Metabolism of 2,4-PD was quite rapid as the concentration of unmetabolized 2,4-PD declined steadily to undetectable after 8 hr. 14C-2,4-PD derived radioactivity was eliminated mainly as 14CO2 and in urine. For the 4.3, 43 and 148.5 mg/kg doses 14CO2 elimination was relatively constant (36.8, 38.8 and 42.3% in 48 hr samples respectively) and greater than urinary excretion (17.9, 14.3 and 29.6%; 48 hr specimens). At 430 mg/kg i.v. there was a reversal of the excretion pattern, with urine 14C excretion (54.7%) becoming greater than that for 14CO2 (27.3%). Excretion in expired volatiles and feces was small. Radiochromatograms of urine showed free 2,4-PD in the 12 hr sample, together with 7 other metabolites. Free 2,4-PD and 6 of the metabolites decreased or were not detectable in a 24 or 48 hr urine sample, but one peak (retention 7.9 min) increased progressively to become the major fraction (97%). Nose-only exposure to 400 ppm 14C-2, 4-PD produced a mean decrease in breathing rate of 20.1%, which was constant and sustained throughout exposure, due to a lengthening of the expiratory phase of the respiratory cycle. 14C-2,4-PD was rapidly absorbed during the first 3 hr of exposure, then began to plateau, but did not reach a steady state. Postexposure elimination of 14C from plasma followed a biexponential form with a t1/2 for the terminal disposition phase of 30.72 hr. Plasma unmetabolized 2,4-PD was present throughout the whole of the exposure phase, but was significantly less than total 14C. Postexposure, plasma unmetabolized 2,4-PD declined rapidly to undetectable concentrations by 12 hr. Radiolabel excretion was approximately equivalent in urine (37.6%) and expired 14CO2 (36.3%). Urine radiochromatograms showed a minor 2,4-PD contaminant (0.6-5.9% over 48 hr), along with 7 other peaks probably representing metabolites. As with the 148.5 mg/kg i.v. dose, the major metabolite peak was at 7.8 min retention, increasing from 41.1% (12 hr) to 62.8% (48 hr). Immediately postexposure, radioactivity was present in all tissues examined, but on a concentration basis (microgram equiv/g) there was no preferential accumulation of 14C in any tissue or organ. On a total organ basis, highest contents were in liver and kidney, presumably related to the metabolism and excretion of 2,4-PD. By 48 hr postexposure, concentrations had decreased in all tissues except fat, presumably due to the lipophilicity of 14C residues. The profile of the plasma-time radioactivity curves, and the presence of residual radioactivity in tissues at 48 hr postexposure, suggests that a cumulative process could occur with frequent repeated exposures.
authors.affiliation: Bushy Run Research Center Export, Pennsylvania, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Frantz
authors.forename: B
authors.initials: B
authors.lastname: Ballantyne
authors.forename: H W
authors.initials: HW
authors.lastname: Leung
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007275:Injections, Intravenous; D008297:Male; D010422:Pentanones / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D002250:Carbon Radioisotopes; D010422:Pentanones; C008790:acetylacetone