Delamanid, a new anti-tuberculosis drug, is metabolized to M1, a unique metabolite formed by cleavage of the 6-nitro-2,3-dihydroimidazo[2,1-b] oxazole moiety, in plasma albumin in vitro. The metabolic activities in dogs and humans are higher than those in rodents. In this study, we characterized the pharmacokinetics and metabolism of delamanid in animals and humans. Eight metabolites (M1-M8) produced by cleavage of the imidazooxazole moiety of delamanid were identified in the plasma after repeated oral administration by liquid chromatography-mass spectrometry analysis. Delamanid was initially catalyzed to M1 and subsequently metabolized by three separate pathways, which suggested that M1 is a crucial starting point. The major pathway in humans was hydroxylation of the oxazole moiety of M1 to form M2 and then successive oxidation to the ketone form (M3) mainly by CYP3A4. M1 had the highest exposure among the eight metabolites after repeated oral dosing in humans, which indicated that M1 was the major metabolite. The overall metabolism of delamanid was qualitatively similar across nonclinical species and humans but was quantitatively different among the species. After repeated administration, the metabolites had much higher concentrations in dogs and humans than in rodents. The in vitro metabolic activity of albumin on delamanid probably caused the species differences observed. We determined that albumin metabolism is a key component of the pharmacokinetics and metabolism of delamanid. Nonhepatic formation of M1 and multiple separate pathways for metabolism of M1 suggest that clinically significant drug-drug interactions with delamanid and M1 are limited.

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Purpose: Dihydropyrimidine dehydrogenase (DPD) deficiency is critical in the predisposition to 5-fluorouracil dose-related toxicity. We recently characterized the phenotypic [2-13 C]uracil breath test (UraBT) with 96% specificity and 100% sensitivity for identification of DPD deficiency. In the present study, we characterize the relationships among UraBT-associated breath C]uracil concentrations were determined over 180 minutes using IR spectroscopy and liquid chromatography-tandem mass spectrometry, respectively. Pharmacokinetic variables were determined using noncompartmental methods. Peripheral blood mononuclear cell (PBMC) DPD activity was measured using the DPD radioassay. Results: The UraBT identified 19 subjects with normal activity, 11 subjects with partial DPD deficiency, and 1 subject with profound DPD deficiency with PBMC DPD activity within the corresponding previously established ranges. UraBT breath Dihydropyrimidine dehydrogenase (EC 1.3.1.2, DPD) is the rate-limiting enzyme in uracil and 5-fluorouracil (5-FU) catabolism, converting >80% of an administered dose of 5-FU to inactive metabolites (1, 2). The initial step of catabolism is mediated by DPD converting 5-FU to 5-dihydrofluorouracil, with subsequent catabolism by dihydropyrimidinase and h-ureidopropionase enzymes to ultimately produce fluoroh-alanine, ammonia, and CO 2 . The latter final metabolic endproducts are excreted in the urine and breath (3).The pharmacogenetic syndrome of complete and partial DPD deficiency is prevalent in f0.1% and 3% to 5% of the general population, respectively (4). DPD deficiency is a significant pharmacogenetic factor in the predisposition of cancer patients to increased risk of altered 5-FU pharmacokinetics and associated toxicity. Specifically, 60% of patients presenting with severe 5-FU-related hematologic toxicity showed reduced DPD activity (5).Recent studies have investigated the predictive value of the ratio of plasma dihydrouracil area under the curve (AUC) to uracil AUC (DUUR) for the assessment of DPD activity and potential individualization of 5-FU therapy. Specifically, 5-FU dose optimization may be based on the plasma DUUR observed before 5-FU administration (6). Jiang et al. have also showed that the pre-5-FU treatment DUUR may be a good index of DPD activity (7,8).Our laboratory recently reported the rapid noninvasive phenotypic [2-13 C]uracil breath test (UraBT) for assessment of DPD activity with 96% specificity and 100% sensitivity (9). Application of the UraBT to a large population of cancer-free subjects (n = 255) showed an observed 86% sensitivity (with 12 of 14 DPD-deficient subjects identified as DPD deficient) and

AimsApproximately 80% of uracil is excreted as b -alanine, ammonia and CO 2 via three sequential reactions. The activity of the first enzyme in this scheme, dihydropyrimidine dehydrogenase (DPD), is reported to be the key determinant of the cytotoxicity and side-effects of 5-fluorouracil. The aim of the present study was to re-evaluate the pharmacokinetics of uracil and its metabolites using a sensitive assay and based on a newly developed, physiologically based pharmacokinetic (PBPK) model. Methods [2-13 C]Uracil was orally administrated to 12 healthy males at escalating doses of 50, 100 and 200 mg, and the concentrations of [2-13 C]uracil, [2-13 C]5,6-dihydrouracil and b -ureidopropionic acid (ureido-13 C) in plasma and urine and 13 CO 2 in breath were measured by liquid chromatography-tandem mass spectrometry and gas chromatograph-isotope ratio mass spectrometry, respectively. Results The pharmacokinetics of [2-13 C]uracil were nonlinear. The elimination half-life of [2-13 C]5,6-dihydrouracil was 0.9-1.4 h, whereas that of [2-13 C]uracil was 0.2-0.3 h. The AUC of [2-13 C]5,6-dihydrouracil was 1.9-3.1 times greater than that of [2-13 C]uracil, whereas that of ureido-13 C was 0.13-0.23 times smaller. The pharamacokinetics of 13 CO 2 in expired air were linear and the recovery of 13 CO 2 was approximately 80% of the dose. The renal clearance of [2-13 C]uracil was negligible. ConclusionA PBPK model to describe 13 CO 2 exhalation after orally administered [2-13 C]uracil was successfully developed. Using [2-13 C]uracil as a probe, this model could be useful in identifying DPD-deficient patients at risk of 5-fuorouracil toxicity.