After oral administration of 14C-labeled idebenone (14C-CV-2619) to rats, the plasma 14C level reached a plateau at 15 min, which persisted till 8 h and then decreased with a half-life of 4.5 h. In dogs, after oral dosing, the plasma 14C peaked at 15 min, followed by biophysical decline with half-lives of 2.2 and 15.4 h. The plasma of both animals contained mostly metabolites, with a small amount of unchanged CV-2619, which was greater than 90% protein-bound. In rats given 14C-CV-2619 orally or intravenously, 14C was distributed widely in tissues, with relatively high concns. in the gut, liver and kidney. CV-2619 readily entered the rat brain to undergo subcellular distribution with a significant amount localized in mitochondria. The concn. of 14C in rat fetus was low, as was that in the milk. Oral 14C-CV-2619 was eliminated by rats and dogs mostly as metabolites within 48 h. In rats, more was excreted in urine than in feces, whereas in dogs excretion by these two routes was almost equal. Enterohepatic cycling of biliary 14C occurred in rats. Repeated oral ingestions of 14C-CV-2619 to rats resulted in no accumulation of 14C. The metabolites found in rats and dogs were QS-10, QS-8, QS-6 and QS-4 formed by oxidative shortening of the side chain of CV-2619, and desmethylated CV-2619 and QS-4. Glucuronides and sulfates of the dihydro (quinol) derivatives of the above metabolites were also detected. Dihydro QS-4 sulfate was the major metabolite in plasma and urine of both animals, while dihydro QS-10 glucuronide was predominant in rat bile.

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Metabolic studies of ipriflavone (TC-80) in rats by gas-liquid chromatography-mass spectrometry led to the characterization of the following metabolites: the parent compound, 7-hydroxy-3-phenyl-4H-1-benzopyran-4-one, 7-hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4one, 3-(4-hydroxyphenyl)-7-isopropoxy-4H-1-benzopyran-4-one, 2-(3-phenyl-4-oxo-4H-1-benzopyran-7-yl)oxypropionic acid, 2-•k3-(4-hydroxyphenyl)-4-oxo-4H-1-benzopyran-7-yl•l oxypropionic acid and 2-•k3-(3-hydroxyphenyl)-4-oxo-4H-1-benzopyran-7-yl•l oxypropionic acid. From the metabolites identified, TC-80 was shown to be metabolized primarily by oxidation. In vitro study using tissue slices of rats indicated that the above metabolic changes occurred exclusively in the liver. It was also demonstrated that the compound did not undergo metabolic conversion by gut flora of rats.

Disposition of [ 14 C]SCE-129 was studied in rats and dogs after intramuscular (i.m.) or intravenous (i.v.) injection. In rats, the plasma level of i.m. [ 14 C]SCE-129 attained a peak at 15 min after dosing and then declined with a half-life of 35 min, whereas the half-life after an i.v. dose was 26 min. The area under the plasma level curve within 2 h after the i.m. dose was 85% of that after the i.v. dose. Intramuscular injection of [ 14 C]SCE-129 into dogs gave a peak plasma level at 30 min and a half-life of 60 min. In both rats and dogs, the plasma levels of 14 C were closely similar to those of the unchanged antibiotic, which was weakly bound to plasma protein. The rat tissue level of i.m. [ 14 C]SCE-129 was maximum at 15 min, with the highest concentration in the kidney, followed by plasma, adrenal, lung, heart, thymus, gastrointestinal wall, and liver, and the lowest in the brain. The antibiotic barely entered erythrocytes of rats and dogs. Whole-body autora-diographic studies showed that i.m. [ 14 C]SCE-129 scarcely crossed the rat placenta. 14 C was detected in the milk of rats given i.m. [ 14 C]SCE-129. In both rats and dogs, almost all of the dosed 14 C was excreted in urine within 24 h as the unaltered antibiotic, with only small amounts appearing in feces via bile. Thus, these findings evidenced a rapid absorption and wide distribution of i.m. SCE-129, followed by extensive renal elimination as the unaltered antibiotic.

The enantioselective pharmacokinetics of a new anxiolytic, pazinaclone (DN-2327), and its active metabolite, M-II, were studied in animals. In rats and dogs given racemic pazinaclone intravenously, the total clearance and volume of distribution of (S)-pazinaclone were lower than those of (R)-pazinaclone, whereas the opposite results were obtained in monkeys. The differences in disposition were consistent with enantioselective protein binding, where the unbound fraction was greater for (R)-pazinaclone than that for the (S)-enantiomer in rats and dogs; the reverse was noted in monkeys. Lower clearance and distribution for (S)-pazinaclone in rats and dogs, and for the (R)-enantiomer in monkeys, resulted in comparable plasma profiles for the pazinaclone enantiomers and thereby those of the corresponding enantiomers of M-II. The unbound clearance (CLu) of (S)-pazinaclone was, however, greater than that of the antipode in rats and dogs and the CLu of each enantiomer was similar in monkeys. Thus, enantioselectivity in the kinetics of (S)- and (R)-pazinaclone appears to reside largely in plasma binding differences and is unrelated to variations in intrinsic clearance. The first-pass metabolism of (S)- and (R)-pazinaclone on oral administration of the racemate was enantioselective, with respective bioavailabilities of 1.7 and 0.8% in rats, 10.4 and 1.9% in dogs, and 0 and 11.4% in monkeys. Therefore, the enantioselectivity was more pronounced after oral dosing.