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).

To ascertain the relationship among 2,5-hexanedione (2,5-HD) concentrations in nerve, serum and urine, rats were injected subcutaneously with 2.6 mmol/kg 2,5-HD alone, or together with 2.6 or 13.0 mmol/kg of methyl ethyl ketone, acetone and toluene. 2,5-HD concentrations in sciatic nerve (NC), serum (SC) and urine (UC) were determined, and the linear regression between each two of NC, SC, and UC were calculated. There was good correlation between NC and SC, SC and UC in the 2,5-HD alone group, and good correlation between NC and SC in the co-treated groups. Co-treatment solvent had little effect on the relationship between SC and NC. 13.0 mmol/kg co-treated solvent tended to decrease the regression coefficients compared with 2.6 mmol/kg co-treated solvent. These results show that SC can be used in estimating NC in the 2,5-HD alone or co-treated groups, and UC can be used in estimating SC in the 2,5-HD alone group.

Coadministration of 2,5-HD with MEK, AC, or TO can increase the concentration and AUC of 2,5-HD in serum and the sciatic nerve, and these increases can be further enhanced by an increase in the concomitant doses of MEK and AC.

The commonly used organic solvents n-hexane and methyl n-butyl ketone (MBK) are often used together with acetone (AC) and/or methyl ethyl ketone (MEK)1-3). The neurotoxic effects of n hexane and MBK or their metabolite 2,5 hexanedione (2,5-HD) are enhanced by the non neurotoxic hydrocarbons acetone and MEK4-16). Many researchers have investigated the mechanisms of this enhancement.Several metabolic studies 12, 17-21) have shown that the metabolism of n-hexane and the toxicokinetics of 2,5-HD could be influenced by MEK, and previ ous studies 15,[22][23][24] suggested that the toxicokinetic changes in 2,5-HD on coadministration with MEK might be associated with their metabolic interaction in the liver.Wigaeus25) reported that the postexposure elimi nation of acetone via the lung is about 20%, small amounts of acetone (approximately 1%) were elim inated unchanged in urine, and that the metabolized amount excreted in urine exceeded 75%. As it has