Influence of Different Doses of Methyl Ethyl Ketone on 2, 5-Hexanedione Concentrations in the Sciatic Nerve, Serum, and Urine of Rats

Abstract

Influence of Different Doses of Methyl Ethyl Ketone on 2, 5-Hexanedione Concentrations in the Sciatic Nerve. Serum, and Urine of Rats: Takato YASUI et al. Department of Public Health and Hygiene. Oita Medical University-Rats were injected subcutaneously with 2, 5-hexanedione (2, 5-HD 2.6m mol/kg) alone (HD group) or with 2, 5-HD and methyl ethyl ketone (MEK) (2.6m mol/kg of each agent, HD&MEK group) or with 2, 5-HD 2.6m mol/kg and 5 times that dose (13.0m mol/kg) of MEK (HD&5MEK group). The concentration of 2, 5-HD in serum and in the sciatic nerve was deter mined 0.5, 1, 2, 4, 8, and 16 h after administration. Urinary 2, 5-HD concentration was determined from the beginning of administration up to 16h after ward. 1) The concentration of 2, 5-HD in the serum, the sciatic nerve, and the urine was increased signi ficantly (p<0.05) in the co-administered groups; the higher the MEK doses were, the greater was the increase. 2) The clearance of 2, 5-HD from both the serum and the sciatic nerve was delayed in the co administered groups. The highest concentration in serum and the sciatic nerve appeared at 1 and 2h respectively. After administration, the biological half life (t1/2) of 2, 5-HD from 1 to 8h in serum was 6.5, 5.8 and 12.0h for the HD, HD&MEK, and HD&5 MEK groups respectively. From 8 to 16h, the t1/2 in serum was 1.2, 3.2 and 16.6h for the HD, HD&MEK, and HD&5MEK groups, respectively. In nerve tissue, the prolongation of clearance in the co administered groups was greater than that in serum, the t1/2 from 2 to 8h being 5.2, 9.6 and 19.9h for the HD, HD&MEK, and HD&5MEK groups, respec tively. From 8 to 16h the t1/2 was 1.0, 3.0 and 16.1 h for the HD, HD&MEK, and HD&5MEK groups, respectively. 3) The average ratios of the 2, 5-HD concentration in the serum/2, 5-HD concentration in the nerve were not significantly different among the three groups (6.2, 5.4, and 6.3 for the HD, HD&MEK and HD&5MEK groups, respectively).

Toxicokinetic interaction of 2,5-hexanedione and methyl ethyl ketone

“…The model, which assumed MEK competitively inhibited 2,5-HD metabolism and elimination, successfully fitted the experimental data of Yasui et al (1995) (Fig. 4).…”

“…In an experiment using rats Table 2 for model parameters]. The symbols represent experimental data from Yasui et al (1995) repeatedly exposed for 7 days, the AUC increased from 549 to 860 lg h/ml in groups receiving 2,5-HD alone and 2,5-HD plus MEK, respectively. Ralston et al (1985) postulated that the increased persistence of 2,5-HD observed in rats was due to competitive inhibition of 2,5-HD by MEK.…”

“…Published data of Yasui et al (1995), which investigated the blood concentration of 2,5-HD as influenced by co-exposure to 2,5-HD and MEK, were selected to estimate model parameters. The authors injected subcutaneously 2.6 mmol/kg 2,5-HD alone or 2.6 mmol/kg 2,5-HD plus MEK at 2.6 mmol/kg or 13 mmol/kg to male Wistar rats.…”

“…where body weights (BW) of rats and humans were based on data reported by Yasui et al (1995) and Liira et al (1990), respectively. Table 1 shows the equivalent volume of distribution of MEK to blood (V MEK =280 ml), which was estimated from physical volumes of the major physiological compartments (including fat, liver, slowperfusion tissue group, rich-perfusion tissue group, and liver) of rats and the tissue/blood partition coefficients of MEK in these compartments.…”

“…The AR program of BMDP statistical software (Dixon 1990) was used to fit experimental concentration data of Yasui et al (1995) and estimate kinetic parameters. The program is a derivative-free nonlinear regression procedure that estimates the parameters for a wide variety of nonlinear functions by the method of least squares (equivalent to the method of maximum likelihood under the assumption of Gaussian errors) using a pseudo-Gauss-Newton iterative algorithm.…”