Tumors may create a state of tolerance toward their own antigens to escape the host’s immune surveillance resulting in failure of cancer immunotherapy. One molecular mechanism by which tumors may inhibit immune responses is via the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan causing inhibition of T cell responses. 1-Methyl-[d]-tryptophan (1MT, NSC 721782) has shown synergistic immune-mediated antitumor effect by inhibiting IDO. The present studies aimed at characterizing pharmacokinetics of 1MT in rodents by using a sensitive LC/MS/MS method with the internal standard α-MT. Incubation of 1MT (250 and 5000 nM) with rat plasma at 370C for 24 h did not produce significant degradation. Plasma protein binding determined by using an ultrafiltration device demonstrated that the free fraction of 1MT (250 and 5000 nM) in rat plasma was 85% and 98%, respectively. A suspension of 1MT in corn oil was prepared for oral dosing, while 7.5 mg/mL of 1MT in saline (pH∼7 adjusted by using dropwise of NaOH and HCI to avoid precipitation) was prepared for i.v. administration. Oral and intravenous administration of 1MT at 12.5 mg/kg (75 mg/m2) to male Fisher rats revealed Cmax 115 uM (i.v.) and 16 uM (p.o.), oral Tmax 5.7 h, t1/2β 16.8 (i.v.) and 13.7 (p.o.) h, Vss 2690 ml/kg, and CL 1.92 (mL/min/kg) with oral bioavailability 87%. Oral and intravenous administration of 1MT at 50 mg/kg (300 mg/m2) to the rats revealed Cmax 320 uM (i.v.) and 37 uM (p.o.), oral Tmax 4.7 h, t1/2β 23.5 (i.v.) and 46 (p.o.) h, Vss 4660 ml/kg, and CL 2.41 (mL/min/kg) with oral bioavailability 109%. Tissue distribution of 1MT following oral administration (100 mg/kg) was investigated in male CD2F1 mice at 1, 5, 10, 24 and 48 h. The highest concentrations of 1MT at 1 and 5 h post-dosing were found in the gastrointestinal tract. The order of tissue concentrations of 1MT entering the systemic circulation were kidney> plasma> liver> muscle> heart> lung and spleen. The lowest concentration was found in the brain (3.6 nmol/g) at 1h. Biphasic disappearance of 1MT with prolonged elimination (t1/2β ≥ 15 h) was observed in heart, lung, small intestine and muscle. The studies concluded that 1MT was stable in plasma. It shows low protein binding, very high oral bioavailability and long elimination t1/2β. Supported by NCI contract N01-CM-07105.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]