Abstract

2,6-Dimethyl-4-benzyl-4-demethylrifampicin (DMB; NSC-143414) is one of a series of semisynthetic rifamycin antibiotics of current interest in cancer chemotherapy because of their activity as inhibitors of viral RNA-directed DNA polymerase. We have studied the absorption, distribution, and excretion of this agent in dogs, rats, and mice. DMB, either unlabeled or labeled with ¹⁴C in the C-38 position, was administered to dogs at 1 or 5 mg/kg orally or iv. The compound was readily absorbed from the gastrointestinal tract, with plasma levels within the therapeutic range (>5 µg/ml) being observed in the dog after oral administration of 1 mg/kg. In all three species, plasma disappearance of DMB administered by the oral, ip, or iv routes was extremely slow (t_½: 2-4 days). In distribution studies in rats, 24 hr after an ip injection of ¹⁴C-DMB (10 mg/kg), high tissue to plasma ratios were found in liver (6.0), pancreas (3.7), and adrenals (7.1); tissues with low levels included fat, muscle, and brain. On subcellular fractionation of rat liver homogenates, the drug was found to be concentrated in the microsomal and mitochondrial fractions. The major excretory route was biliary, yet only 4.1 ± 0.4% of the dose (mean ± SE) was found in bile within 24 hr in the rat (10 mg of DMB per kg; N = 4); bile radioactivity was found on thin-layer chromatography to consist largely of unchanged DMB and the corresponding DMB-naphthoquinone, although lesser amounts of three metabolites were detectable. No circulating metabolites, other than trace amounts of the naphthoquinone form of DMB, were detected by thin-layer chromatography of serum extracts. The slow plasma disappearance of circulating DMB in all species examined may be a consequence of plasma protein binding: the DMB-albumin association constants at pH 7.4 were 2.3 x 10⁴, 3.5 x 10⁵, and 7.6 x 10⁴ M^-1 for dog, rat, and bovine plasma albumin, respectively. The major significant features of the physiological disposition of DMB in the mammalian species studied are its extremely slow plasma disappearance, its extensive plasma protein binding, its prolonged tissue retention, and its excretion primarily by the biliary rather than the urinary route.