A B S T R A C T The mean half-life of antipyrine in the plasma of four sets of identical and four sets of fraternal twins after a single oral dose of 16 mg/kg of antipyrine was 12.7 ±SD 3.3 hr. After 2 wk on sodium phenobarbital (2 mg/kg daily) the half-life of antipyrine in the plasma of these twins was reduced to 8.0 ±SD 1.5 hr. Shortening of the plasma antipyrine half-life occurred in all but one of these 16 normal, adult volunteers, but there was considerable variation in the extent of reduction which ranged from 0 to 69%. Phenobarbital administration decreased individual variations in antipyrine metabolism as indicated by the smaller standard deviation of the plasma antipyrine half-lives after phenobarbital than observed initially and by the narrowed range of variation in plasma antipyrine half-lives from 2.8-fold initially to 1.8-fold after phenobarbital. These twins indicate genetic, rather than environmental, control of phenobarbital-induced alterations in plasma antipyrine half-life.

With the recent approval of 17-DMAG for clinical use, the data generated from these preclinical studies will provide guidance to clinicians as they administer this drug to their patients. The MTD of 17-DMAG was 12 mg/m2 per day in rats and 8 mg/m2 per day in dogs; therefore, the recommended starting dose for phase I trial is 1.3 mg/m2 per day for 5 days. Gastrointestinal and bone marrow toxicity were dose-limiting in rats, and gastrointestinal, renal, gallbladder and bone marrow toxicity were dose-limiting in dogs. All adverse effects were fully reversible in surviving animals after treatment was complete.

Antipyrine was administered to identical or monozygotic twins and to fraternal or dizygotic twins. Individuals with identical genotypes (monozygotic twins) exhibited significantly less variability in antipyrine halflife than did genetically different individuals (dizygotic twins). Therefore variations in antipyrine metabolism appear to be determined genetically rather than environmentally. In the 36 twins tested, antipyrine half-lives varied between 5.1 and 16.7 hours. No significant correlation occurred between half-lives for phenylbutazone and antipyrine in the 28 twins who received both drugs.

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 greater susceptibility of humans and dogs to the myelotoxicity of camptothecins, compared to mice, was evident in vitro at the cellular level. Differential sensitivity between murine and human myeloid progenitors explains why the curative doses of TPT and 9AC in mice with human tumor xenografts are not achievable in patients. Realizing the curative potential of these compounds in humans will require the development of therapies to increase drug tolerance of human CFU-GM at least to a level equal to that of murine CFU-GM. Because these interspecies differences are complicated by species-specific effects of plasma proteins on drug stability, not all in vitro assay conditions will yield results which can contribute to the development of such therapies.