The pharmacokinetics of the quinazoline antifolate ICID 1694 in mice and rats

Abstract

N-(5-[N-(3,4-Dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N- methylamino]-2-thenoyl)-L-glutamic acid (ICI D1694) is an analogue of the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717). CB3717 was found to be an active anticancer agent in early clinical studies, but its use was limited by its relative insolubility at physiological pH. ICI D1694 has been shown to be a more active anticancer agent than CB3717 in model systems, and it is devoid of the acute renal toxicity associated with the administration of the latter drug to mice. In the present study, the pharmacokinetics of ICI D1694 were studied in both mice and rats using reverse-phase HPLC. In rats, ICI D1694 clearance (CL) conformed to a two-compartment open model and was rapid (CL = 10.7 ml min-1 kg-1, t1/2 beta = 30 min). Excretion was mainly biliary (65% of the delivered dose in 4 h vs 12% in urine) in the rat following a 100-mg/kg i.v. bolus. A high degree of protein binding was seen in rat plasma (greater than or equal to 90% over the range of 20-100 microM). In mice, ICI D1694 CL = 27 ml min-1 kg-1 and t1/2 beta = 30 min following 100 mg/kg i.v., which was significantly faster than CB3717 clearance (CL = 6 ml min-1 kg-1, t1/2 beta = 93 min). ICI D1694 was fully bioavailable following i.p. administration (AUC = 3.73 mg ml-1 min i.v. 4.03 mg ml-1 min i.p.), but its bioavailability following oral administration appeared to be low (approximately 10%-20%). Tissue distribution and excretion studies in mice suggested that biliary excretion predominated, confirming the results obtained in rats. Following an i.v. dose of 500 mg/kg ICI D1694 in mice, drug was detectable at 24 h, suggesting the presence of a third phase of plasma clearance. The initial HPLC assay could not detect this third phase following a dose of 100 mg/kg; hence, a more sensitive assay was developed that includes a solid-phase extraction step. The latter assay was used to define the third phase of ICI D1694 clearance in mice, and preliminary studies demonstrated a terminal half-life of 6.5 +/- 2.7 h.

Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models

“…The calculated half-life is similar to previous estimates determined by HPLC but after a much higher dose (100 mg kg-' i.p.) (Jodrell et al, 1991). Further, evidence of a slower phase of elimination has been obtained in this study and, after 100 mg kg-', plasma concentrations of ZD1694 were still measurable at least 7 days after drug administration.…”

“…Because of the high potency of ZD1694 and its rapid elimination from plasma (Jackman et al, 1991a;Jodrell et al, 1991), a highly sensitive assay is required for extended pharmacokinetic studies; radioimmunoassay offers an attractive altemative to HPLC. A sheep antiserum to ZD1694 has been used for the radioimmunoassay of plasma samples and it is specific and sensitive with consistent day-to-day performance.…”

“…A sheep antiserum to ZD1694 has been used for the radioimmunoassay of plasma samples and it is specific and sensitive with consistent day-to-day performance. As there is as yet no evidence of plasma and urinary metabolites of ZD1694 (Jodrell et al, 1991;Judson et al, 1996), plasma drug measurements made with the antiserum can be considered to be specific for ZD1694. The remarkable ability of antisera to distinguish between antifolates and natural folates has been shown before (Levine and Powers, 1974;Aheme et al, 1977) and the low cross-reaction of the ZD1694 antiserum with reduced folates was therefore not surprising.…”

“…ZD1694 has previously been measured in plasma by reversedphase HPLC (Jodrell et al, 1991). The limit of detection of this assay for plasma was 0.2 g1M when a solid-phase extraction was used.…”

TomudexTM (ZD1694): from concept to care, a programme in rational drug discovery

“…injection of 5 mg/kg (plasma ZD1694 ,-~0.01 #M) [70]. These tissue levels explain why a drug which is rapidly eliminated from the plasma (tl/2fl of 30 min) [71] elicits sustained biological effects. Thus, TS was inhibited (rate of 3H release from 5-3H dUrd) in L 1210 ascitic tumour cells grown in mice for at least 24 hr after a single i.v.…”