EFFECTS OF METHYL ETHYL KETONE, ACETONE, OR TOLUENE COADMINISTRATION ON 2,5-HEXANEDIONE CONCENTRATION IN THE SCIATIC-NERVE, SERUM, AND URINE OF RATS

Objective: To clarify changes in the serum, nerve, and urinary levels of 2,5-hexanedione (2,5-HD) in rats on coadministration with methyl et hyl ketone (MEK), acetone (AC), and toluene (TO). Method: 2,5-HD alone or combined with MEK, AC, and TO was injected subcutaneously into a t otal of 306 male Wistar rats. The rats were divided as follows into 7 groups: (1) 2.6 mmol/kg 2,5-HD alone (HD) and (2) 2.6 mmol/kg 2,5-HD c ombined with 2.6 mmol/kg MEK (HD + MEK), (3) with 2.6 mmol/kg AC (HD AC), (4) with 2.6 mmol/kg TO (HD + TO), (5) with 13.0 mmol/kg MEK (HD + 5MEK), (6) with 13.0 mmol/kg AC (HD + 5AC), and (7) with 13.0 mmol/ kg TO (HD + 5TO). 2,5-HD concentrations in the serum, sciatic nerve, a nd urine of rats were determined within 16 h of the injections and pha rmacokinetic parameters were estimated. Results: It was observed that (1) the 2,5-HD concentration and AUC value (area under concentration v ersus time curve) determined in the serum and nerve increased signific antly in the cotreated groups as compared with the HD group; (2) the e ffect MEK had in elevating the 2,5-HD concentration and AUC in the ser um and nerve was stronger than that of AC, and the effect AC had was s tronger than that of TO; (3) a dose increase from 2.6 to 13.0 mmol/kg for MEK and AC induced further increases in the 2,5-HD concentration a nd AUC determined in the serum and nerve; (4) elimination constants re corded for 2,5-HD (K-e) from the serum and nerve decreased in all the cotreated groups, and the degree of the decrease correlated inversely with the elevation in 2,5-HD concentration and AUC in the serum and ne rve; and (5) urinary 2,5-HD concentrations measured in the 13.0-mmol/k g cotreated groups increased in parallel with the elevation in serum 2 ,5-HD concentrations. Conclusion: Coadministration of 2,5-HD with MEK, AC, or TO can increase the concentration and AUC of 2,5-HD in serum a nd the sciatic nerve, and these increases can be further enhanced by a n increase in the concomitant doses of MEK and AC.