The effect of buthionine sulphoximine, cimetidine and phenobarbitone on the disposition of amsacrine in the rabbit.
Evidence suggests that the main elimination pathway for amsacrine is hepatic oxidation to the quinone diimine derivative followed by conjugation with glutathione (GSH) and excretion in the bile. If this is so, amsacrine elimination should be susceptible to induction by phenobarbitone (PB) and inhibition by cimetidine (CT) and perhaps by buthionine sulphoximine (BSO), a specific depleter of tissue GSH. This study was carried out in groups of six rabbits. Each rabbit acted as its own control and received pretreatment with saline or PB, CT, or BSO, followed by an amsacrine infusion. Blood (8 X 3 mL) was collected up to 12 h and total plasma amsacrine concentrations determined by HPLC. PB pretreatment resulted in a significant increase in amsacrine's Cl (mean 46%, range 25%-70%) and also in the Vd (mean 58%, range 25%-117%), but had no effect on t1/2 alpha, t1/2 beta or MRTni. In addition, there was no change in the plasma protein binding of amsacrine after PB pretreatment. CT pretreatment had the opposite effect, resulting in a significant decrease in amsacrine's Cl (mean 33%, range 21%-38%) and a decrease in Vd, although this latter decrease was not significant at the 5% level. As with PB, the time parameters were not significantly changed. BSO pretreatment resulted in a significantly reduced Cl (mean 22%, range 15%-30%), no effect on Vd or on t1/2 alpha, but significantly prolonged t1/2 beta and MRTni. BSO pretreatment was also associated with a significant reduction in red blood cell GSH concentration. These results are consistent with the involvement of the hepatic mixed function oxidase system and GSH status in the elimination of amsacrine in the rabbit.
D000677:Amsacrine / Q000097:blood / Q000378:metabolism*; D000818:Animals; D019328:Buthionine Sulfoximine; D002927:Cimetidine / Q000494:pharmacology*; D004912:Erythrocytes / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D011817:Rabbits
D000677:Amsacrine; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D002927:Cimetidine; D006899:Mixed Function Oxygenases; D005978:Glutathione; D010634:Phenobarbital