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Cancer Chemotherapy and Pharmacology

, Volume 28, Issue 5, pp 331–338 | Cite as

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

  • D. I. Jodrell
  • D. R. Newell
  • W. Gibson
  • L. R. Hughes
  • A. H. Calvert
Original Articles Pharmacokinetics, ICI D1694, Antifolate, Quinazoline

Summary

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 inhibitorN10-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 CB 3717 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,t1/2β=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 (≥90% over the range of 20–100 μm). In mice, ICI D1694CL=27 ml min−1 kg−1 andt1/2β=30 min following 100 mg/kg i.v., which was significantly faster than CB3717 clearance (CL=6 ml min−1 kg−1,t1/2β=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 24h, 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.

Keywords

Plasma Clearance Biliary Excretion Quinazoline HPLC Assay Early Clinical Study 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • D. I. Jodrell
    • 2
  • D. R. Newell
    • 2
  • W. Gibson
    • 2
  • L. R. Hughes
    • 1
  • A. H. Calvert
    • 2
  1. 1.ICI PharmaceuticalsMacclesfieldUK
  2. 2.Drug Development Section, E BlockInstitute of Cancer ResearchSuttonUK

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