Toxicology and pharmacokinetics of 1-methyl-d-tryptophan: Absence of toxicity due to saturating absorption

Abstract

Abstract1-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 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 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/m 2 /day (25 to 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 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.

The Conduct of Drug Metabolism Studies Considered Good Practice (II): In Vitro Experiments

“…Some drugs considered CYP substrates did not show the concentration-related stability under the same condition [18]. Drugs that are not the substrates of CYPs are usually stable in microsomal incubation and their stability will not be affected by their incubating concentrations [25]. It is prudent to set up at least two concentrations of a test drug (e.g., 1 and 10 μM) to determine if the drug's concentration has any effect on its own stability in microsomes and other biomatrices.…”

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

“…53 1-MT appears to have little, if any, toxicity issues and is currently being developed for use as a vaccine adjuvant and combination chemotherapeutic agent. 54 However, further insight into the role of downstream kynurenine pathway metabolites in this pathophysiological process is still needed to fully understand this longstanding and very complex process.…”

Chemotherapeutic Agents in Cancer Treatment and Tryptophan Metabolism

“…The authors also reported that the in vivo effects were IDO-gene dependent and concluded that 1-D-MT is the suitable choice of IDO inhibitor to be incorporated into human chemo-immunotherapy regimens. Subsequent evaluation of pharmacokinetics and toxicity of oral 1-D-MT in rats and dogs revealed that the application of 1-D-MT is safe with very little toxicity (Jia et al 2008 ). Yet, Löb et al and Qian et al suggested that 1-L-MT is more benefi cial than 1-D-MT in reversing IDO-mediated proliferation arrest and tryptophan depletion (Lob et al 2009 ;Qian et al 2009 ).…”