THE RENAL EFFECTS OF THE WATER-SOLUBLE, NON-FOLYLPOLYGLUTAMATE SYNTHETASE DEPENDENT THYMIDYLATE SYNTHASE INHIBITOR ZD9331 IN MICE

ZD9331 is a novel, potent thymidylate synthase (TS) inhibitor which do es not require polyglutamation by folylpolyglutamate synthetase (FPGS) for its activity. In contrast to Tomudex (ZD1694), ZD9331 may therefo re be active against tumours with low FPGS activity. ZD9331 shows anti -tumour activity by both 24-h infusion and bolus administration in the murine thymidine kinase-deficient (TK -/-) lymphoma L5178Y. In view o f the history of renal toxicity with some earlier TS inhibitors and th e possible therapeutic use of bolus ZD9331, we have examined the effec ts of bolus ZD9331 dose and route of administration on plasma and kidn ey pharmacokinetics and renal function in mice. Renal function was ass essed by measuring [C-14]inulin clearance, and drug concentrations wer e assayed by reverse-phase high-performance liquid chromatography (HPL C). Renal function was unaffected by ZD9331 up to 150 mg kg(-1) either i.v. or i.p. However, at 200 mg kg(-1), glomerular filtration rate wa s significantly inhibited following i.v. but not i.p. administration. Pharmacokinetic studies showed that these effects were consistent with the markedly higher plasma drug concentrations occurring during early times following i.v. dosing, although the plasma drug profiles were o therwise similar for both routes. Kidney drug concentrations were slig htly elevated in i.v.- versus i.p.-treated animals at the low dose (50 mg kg-l), with a correspondingly larger area under the curve. However , at the highest dose (200 mg kg(-1)), peak kidney drug concentrations were 20-fold higher following i.v. administration than after i.p., wi th marked kidney retention, resulting in a 50-fold greater kidney drug exposure for the i.v. versus the i.p. route. These data show that ZD9 331 is non-nephrotoxic at active anti-tumour doses (50 mg kg-l i.p.) i n mice, and only at very high bolus i.v. doses is there impaired renal function as a result of very high peak plasma concentrations. These a dverse effects can be readily overcome by i.p. administration, indicat ing the likely need for short infusions in clinical settings.