The effect of cimetidine, phenobarbitone and buthionine sulphoximine on the disposition of N-5-dimethyl-9-[(2-methoxy-4-methyl-sulphonylamino)phenylamino]- 4-acridinecarboxamide (CI-921) in the rabbit.
N-5-dimethyl-9-[(2-methoxy-4-methylsulphonyl-amino)phenylamino]-4- acridinecarboxamide (CI-921) is an amsacrine analogue currently undergoing phase II clinical trials as an antitumor drug. Significant alterations in the plasma clearance (CL) of amsacrine have been demonstrated in rabbits after pretreatment with cimetidine (CT), phenobarbitone (PB) and buthionine sulphoximine (BSO). In the present study, the influence of these agents on the disposition of CI-921 was investigated in rabbits. After a short infusion of CI-921 (12.7 mumol/kg), blood (8 x 3 ml) was collected up to 12 h and the total plasma concentration of CI-921 determined by HPLC. Model-independent pharmacokinetic parameters were compared by Student's paired t-test. CT pretreatment significantly (P = 0.011) increased the AUC (mean, 21%; range, 3%-43%) and significantly (P = 0.019) decreased the CL (mean, 17%; range, 4%-30%). The induction effect of PB pretreatment was not confirmed with CI-921. No significant reduction in AUC or increase in CL was apparent. BSO pretreatment caused a small but significant (P = 0.049) increase in AUC (mean, 20.5%; range, 4%-59%) but had no effect on CL. Although more modest changes in kinetic parameters were observed with CI-921 than with amsacrine, these results suggested the involvement of the hepatic mixed-function oxidase system but not PB-inducible cytochrome P-450 isozymes in the elimination of CI-921 in the rabbit. As with amsacrine, a reduction in hepatic glutathione (GSH) concentrations in the body also appeared to have a modest effect on the disposition of CI-921.
Paxton
J W
JW
Department of Pharmacology and Clinical Pharmacology, University of Auckland School of Medicine, New Zealand.
Evans
P C
PC
Hardy
J R
JR
D000677:Amsacrine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019328:Buthionine Sulfoximine; D002927:Cimetidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005978:Glutathione / Q000097:blood; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology*; D011817:Rabbits; D013997:Time Factors
D000963:Antimetabolites; D000970:Antineoplastic Agents; D000677:Amsacrine; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D002927:Cimetidine; D005978:Glutathione; C042315:asulacrine; D010634:Phenobarbital