Changes in 2,5‐Hexanedione Concentration in the Sciatic Nerve, Serum and Urine of Rats Induced by Combined Administration of 2,5‐Hexanedione with Acetone or Methyl Ethyl Ketone

Abstract

Changes in 2,5‐Hexanedione Concentration in the Sciatic Nerve, Serum and Urine of Rats Induced by Combined Administration of 2,5‐ Hexanedione or Methyl Ethyl Ketone: Kazuo Aoki, et al. Department of Public Health and Hygiene, Oita Medical University—To clarify whether there is a difference in the toxicokinetic changes in 2,5‐ hexanedione (2,5‐HD) on coadministration with acetone or methyl ethyl ketone (MEK), 108 rats were treated subcutaneously with 2,5‐HD at a dose of 2.6 mmol/kg alone (HD group), with 2,5‐HD and acetone both at 2.6 mmol/kg (HD + AC group), or with 2,5 ‐HD and MEK both at 2.6 mmol/kg (HD + MEK group). At 0.5, 1, 2, 4, 8, and 16 hours after injection, 2,5‐HD concentrations in serum, the sciatic nerve and urine (16 hours only) were determined and some toxicokinetic parameters were then estimated. The 2,5‐HD concentrations in serum and the sciatic nerve were significantly higher in both the coadministered groups at 16 hours, and the AUC (area under the serum or nerve concentration versus time curve) in serum and the sciatic nerve of both the coadministered groups increased significantly during 8 to 1 6 hours compared with the 2,5‐HD alone group. The differences in urinary 2,5‐HD concentrations among the three groups were at the marginal level for significance by ANOVA (p = 0.053), but the values for the total amount of urinary 2,5‐HD within 16 hours were not significantly different (p = 0.55) among the three groups. There were good correlations between 2,5‐HD concentrations in the sciatic nerve and those in serum in the three groups (r = 0.91, r = 0.91 and r = 0.85 for HD, HD + AC and HD + MEK groups, respectively). The ratios of 2,5‐HD concentration in the sciatic nerve/2,5‐HD concentration in serum were not significantly different among the three groups (0.17, 0.19 and 0.20 for HD, HD + AC and HD + MEK groups, respectively). The estimated biological halflife t1/2 in the HD + AC group was prolonged significantly as was that in the HD + MEK group when compared with that in the HD alone group. The retarded elimination of 2,5‐HD from serum seemed not to be directly related to urinary excretion in the coadministered groups. The present study revealed that the coadministration of 2,5‐HD with acetone produced similar toxicokinetic changes in serum and in the sciatic nerve as that with MEK. It was suggested that the retardation of disappearance of 2,5‐HD from serum and the sciatic nerve on administration of a combination of 2,5‐HD with acetone was not related to urinary excretion but to the overloading of the metabolic capacity of 2,5‐HD in the liver.