TY - JOUR
T1 - Toxicology and pharmacokinetics of 1-methyl-d-tryptophan
T2 - Absence of toxicity due to saturating absorption
AU - Jia, Lee
AU - Schweikart, Karen
AU - Tomaszewski, Joseph
AU - Page, John G.
AU - Noker, Patricia E.
AU - Buhrow, Sarah A.
AU - Reid, Joel M.
AU - Ames, Matthew M.
AU - Munn, David H.
N1 - Funding Information:
The studies were supported by NCI Contract Funds NO1-CM-07105, NO1-CM-52206, and NO1-CM-42201.
Funding Information:
D-1MT (NSC 721782) was synthesized under contract with the National Cancer Institute. The purity of D-1MT was determined to be 98–99% by a chiral HPLC method, and lot Nos. F68/L-1 to F68/L-9 were used in the present studies. Animals were handled in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996), or the Principles of Laboratory Animal Care ( http://history.nih.gov/laws ).
PY - 2008/1
Y1 - 2008/1
N2 - 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 24 h produced no significant degradation, with <15% of D-1MT being bound to plasma protein. Following oral administration, D-1MT exhibited a larger AUC and Vd, longer elimination t1/2, and slower clearance in rats than in dogs. When oral doses of D-1MT exceeded levels of 600 mg/m2/day in rats, or 1200 mg/m2/day in dogs, the Cmax 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 t1/2 of 6.0 h and 28.7 h, a Tmax of 1 h and 8 h, 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/m2/day (25-500 mg/kg/day) and in dogs from 600 to 1200 mg/m2/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/m2/day were the no-observed-adverse-effect levels in rats and dogs, respectively. Mean plasma concentrations of D-1MT (600 and 1200 mg/m2/day) in dogs 1 h post dosing were 54.4 and 69.5 μg/ml on Day 1, respectively, and 53.1 and 66.6 μg/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.
AB - 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 24 h produced no significant degradation, with <15% of D-1MT being bound to plasma protein. Following oral administration, D-1MT exhibited a larger AUC and Vd, longer elimination t1/2, and slower clearance in rats than in dogs. When oral doses of D-1MT exceeded levels of 600 mg/m2/day in rats, or 1200 mg/m2/day in dogs, the Cmax 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 t1/2 of 6.0 h and 28.7 h, a Tmax of 1 h and 8 h, 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/m2/day (25-500 mg/kg/day) and in dogs from 600 to 1200 mg/m2/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/m2/day were the no-observed-adverse-effect levels in rats and dogs, respectively. Mean plasma concentrations of D-1MT (600 and 1200 mg/m2/day) in dogs 1 h post dosing were 54.4 and 69.5 μg/ml on Day 1, respectively, and 53.1 and 66.6 μg/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.
KW - 1-methyl-d-tryptophan
KW - Indoleamine 2,3-dioxygenase
KW - Pharmacokinetics
KW - Saturating absorption
KW - Toxicity
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UR - http://www.scopus.com/inward/citedby.url?scp=36849049268&partnerID=8YFLogxK
U2 - 10.1016/j.fct.2007.07.017
DO - 10.1016/j.fct.2007.07.017
M3 - Article
C2 - 17868966
AN - SCOPUS:36849049268
SN - 0278-6915
VL - 46
SP - 203
EP - 211
JO - Food and Chemical Toxicology
JF - Food and Chemical Toxicology
IS - 1
ER -