Preclinical pharmacology of CB30900, a novel dipeptide inhibitor of thymidylate synthase, in mice.
CB30900 is a novel, potent thymidylate synthase inhibitor which can not be polyglutamated and may be active in cancers expressing low or defective folylpolyglutamate synthetase. Pharmacokinetics were studied in mouse tumors and tissues after bolus or infusion protocols. Elimination was triphasic after 100 mg kg-1 i.v. (T 1/2 alpha, 2.8 min; T 1/2 beta, 19.1 min and T 1/2 gamma, 4.1 hr). Peak concentrations were 716 microM; clearance, 1.19 ml g-1 hr-1; and area under the curve (AUC 0-2 hr), 131 microM hr. Biphasic elimination occurred after i.p. administration and was comparable to the i.v. route giving complete i.p. bioavailability. Kidney concentrations were similar to plasma (AUC 0-2 hr, 84.3 microM hr). CB30900 concentrations in the gut increased steadily with time (AUC 0-2 hr, 645 microM hr) and liver drug concentrations were 7-fold greater than plasma (AUC 0-2 hr, 847 microM hr). Peak tumor concentrations occurred at 30 min and were 27% of plasma concentrations, but tumor drug clearance was markedly slower than for plasma (T 1/2, 51 +/- 8.2 min, mean +/- S.E.). CB30900 was remarkably stable in vivo with 93% of an administered dose recovered unchanged after 48 hr. Plasma drug binding was concentration-dependent, ranging from 93.3 to 76% over 1 to 500 microM. During 24 hr infusion (50 mg kg-1 s.c.), steady-state plasma concentrations were 3 microM, giving an AUC 0-24 hr of 71 microM hr. Kidney drug levels were similar to plasma but liver concentrations were elevated 7-fold. By contrast, tumor drug concentrations were about 0.5 microM (AUC 0-24 hr, 14.6 microM hr). However, these low plasma drug concentrations are growth inhibitory in vitro (24-hr exposure).
Walton
M I
MI
CRC Centre for Cancer Therapeutics, Sutton, Surrey, UK.
Gibson
W
W
Aherne
G W
GW
Lawrence
N
N
Stephens
T C
TC
Smith
M N
MN
Jackman
A L
AL
D000818:Animals; D004151:Dipeptides / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism; D008223:Lymphoma / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D008811:Mice, Inbred DBA; D011485:Protein Binding; D011799:Quinazolines / Q000493:pharmacokinetics*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution
D004151:Dipeptides; D004791:Enzyme Inhibitors; D011799:Quinazolines; C099176:CB 30900; D013940:Thymidylate Synthase