Abstract

The metabolism of delamanid (OPC-67683, Deltyba), a novel treatment of multidrug-resistant tuberculosis, was investigated in vitro using plasma and purified protein preparations from humans and animals. Delamanid was rapidly degraded by incubation in the plasma of all species tested at 37°C, with half-life values (hours) of 0.64 (human), 0.84 (dog), 0.87 (rabbit), 1.90 (mouse), and 3.54 (rat). A major metabolite, (R)-2-amino-4,5-dihydrooxazole derivative (M1), was formed in the plasma by cleavage of the 6-nitro-2,3-dihydroimidazo(2,1-b)oxazole moiety of delamanid. The rate of M1 formation increased with temperature (0−37°C) and pH (6.0−8.0). Delamanid was not converted to M1 in plasma filtrate, with a molecular mass cutoff of 30 kDa, suggesting that bioconversion is mediated by plasma proteins of higher molecular weight. When delamanid was incubated in plasma protein fractions separated by gel filtration chromatography, M1 was observed in the fraction consisting of albumin, γ-globulin, and α₁-acid glycoprotein. In pure preparations of these proteins, only human serum albumin (HSA) metabolized delamanid to M1. The formation of M1 followed Michaelis-Menten kinetics in both human plasma and the HSA solution, with similar K_m values: 67.8 µM in plasma and 51.5 µM in HSA. The maximum velocity and intrinsic clearance values for M1 were also comparable in plasma and HSA. These results strongly suggest that albumin is predominantly responsible for metabolizing delamanid to M1. We propose that delamanid degradation by albumin begins with a nucleophilic attack of amino acid residues on the electron-poor carbon at the 5 position of nitro-dihydro-imidazooxazole, followed by cleavage of the imidazooxazole moiety to form M1.