title: Pharmacokinetic/pharmacodynamic study of ZD9331, a nonpolyglutamatable inhibitor of thymidylate synthase, in a murine model following two curative administration schedules.
abstract: ZD9331 is a nonpolyglutamatable antifolate inhibitor of thymidylate synthase currently in clinical development. This enzyme is crucial for DNA synthesis and catalyzes the reductive methylation of dUMP to form thymidylate, which is subsequently converted to dTTP. The pharmacokinetics of two curative antitumor doses of ZD9331 administered by either a single i.p. bolus injection (50 mg/kg) or by 24-h s.c. infusion (3 mg/kg) have been measured in a thymidine salvage-incompetent murine lymphoma model (L5178Y) using a sensitive and specific ELISA. To gain an understanding of the relationship between the pharmacokinetics of ZD9331 and antitumor activity perturbations in tumor, dTTP and dUMP concentrations were also determined. After bolus administration, ZD9331 was eliminated from plasma and tissues relatively rapidly, with terminal elimination (lambda(z) 0-24 h) of 4-6 h. Liver concentrations were 8-fold higher than those measured in the plasma. Kidney and lymphoma drug concentrations were similar to those of plasma, although there was evidence of a slower overall elimination of drug at later time points. Steady-state concentrations of ZD9331 were obtained 4-5 h after the start of the 24 h s.c. infusion. At the end of infusion, elimination rates were similar for plasma and tissues (approximately 3.5 h) but appeared to be slower in the tumor at later time points. Liver concentrations were approximately 4-fold higher, and kidney and tumor concentrations were similar to those in the circulation. Depletion of dTTP and elevation in dUMP in the tumor were consistent with inhibition of thymidylate synthase after both administration schedules, although the time for which dTTP was decreased was longer (approximately 24 h) for the infusional route than for the bolus injection (<16 h). The results suggest that antitumor activity is dependent on attaining adequate drug concentrations to affect dTTP pools as well as on the duration of effective drug levels.
authors.affiliation: Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, United Kingdom. wynne@icr.ac.uk
authors.forename: G W
authors.initials: GW
authors.lastname: Aherne
authors.forename: A
authors.initials: A
authors.lastname: Hardcastle
authors.forename: E
authors.initials: E
authors.lastname: Ward
authors.forename: D
authors.initials: D
authors.lastname: Dobinson
authors.forename: T
authors.initials: T
authors.lastname: Crompton
authors.forename: M
authors.initials: M
authors.lastname: Valenti
authors.forename: L
authors.initials: L
authors.lastname: Brunton
authors.forename: A L
authors.initials: AL
authors.lastname: Jackman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D003854:Deoxyribonucleotides / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007260:Infusion Pumps; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D003854:Deoxyribonucleotides; D011799:Quinazolines; C094299:ZD 9331; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase