Toxicology and pharmacokinetics of 1-methyl-d-tryptophan: absence of toxicity due to saturating absorption.
1-methyl-d-tryptophan (D-1MT) reverses the immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO), and it is currently being developed both as a vaccine adjuvant and as an immunotherapeutic agent for combination with chemotherapy. The present study examined the pharmacokinetics and toxicity of D-1MT in preparation for clinical trials. Incubation of D-1MT in rat plasma for 24h produced no significant degradation, with <15% of D-1MT being bound to plasma protein. Following oral administration, D-1MT exhibited a larger AUC and V(d), longer elimination t(1/2), and slower clearance in rats than in dogs. When oral doses of D-1MT exceeded levels of 600 mg/m(2)/day in rats, or 1200 mg/m(2)/day in dogs, the C(max) and AUC values decreased, resulting in a corresponding decrease in oral bioavailability. Thus, the doses were indicative of the lowest saturating doses in dogs and rats corresponding with an elimination t(1/2) of 6.0 h and 28.7 h, a T(max) of 1h and 8h, and a bioavailability of 47% and 92%, respectively. Tissue concentrations of D-1MT in mice were highest in the kidney, followed by the liver, muscle, heart, lung, and spleen, respectively; 48 h post dosing, D-1MT was excreted in the urine (35.1%) and feces (13.5%). Oral administration of D-1MT in rats from 150 to 3000 mg/m(2)/day (25-500 mg/kg/day) and in dogs from 600 to 1200 mg/m(2)/day (30 and 60 mg/kg/day) for 28 consecutive days did not lead to mortality, adverse events, histopathological lesions, or significant changes in hematology, clinical chemistry, and body weight. These results suggested that 3000 and 1200 mg/m(2)/day were the no-observed-adverse-effect levels in rats and dogs, respectively. Mean plasma concentrations of D-1MT (600 and 1200 mg/m(2)/day) in dogs 1h post dosing were 54.4 and 69.5 microg/ml on Day 1, respectively, and 53.1 and 66.6 microg/ml on Day 28, respectively; thus, indicating no increase in plasma D-1MT with a change in dose. In conclusion, D-1MT has little toxicity when administered orally to rats and dogs. Exceeding the saturating dose of D-1MT is unlikely to cause systemic toxicity, since any further increase in D-1MT plasma levels would be minimal.
Jia
Lee
L
Developmental Therapeutics Program, National Cancer Institute, Rm 8042, 6130 Executive Blvd., Bethesda, MD 20852, USA. jiale@mail.nih.gov
Schweikart
Karen
K
Tomaszewski
Joseph
J
Page
John G
JG
Noker
Patricia E
PE
Buhrow
Sarah A
SA
Reid
Joel M
JM
Ames
Matthew M
MM
Munn
David H
DH
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D002138:Calibration; D004285:Dogs; D006207:Half-Life; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D051379:Mice; D019055:No-Observed-Adverse-Effect Level; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D014018:Tissue Distribution; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity
D001798:Blood Proteins; C028129:tryptophan methyl ester; D014364:Tryptophan