The Absorption, Metabolism, and Excretion of the Novel Neuromodulator RWJ-333369 (1,2-Ethanediol, [1-2-Chlorophenyl]-, 2-carbamate, [S]-) in Humans

Abstract

RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-; CAS Registry Number 194085-75-1) is a novel neuromodulatorin clinical development for the treatment of epilepsy. To study the disposition of RWJ-333369, eight healthy male subjects received a single oral dose of 500 mg of 14 C-RWJ-333369. Urine, feces, and plasma were collected for analysis for up to 1 week after dosing. Radioactivity was mainly excreted in urine (93.8 ؎ 6.6%) and much less in feces (2.5 ؎ 1.6%). RWJ-333369 was extensively metabolized in humans, since only low amounts of parent drug were excreted in urine (1.7% on average) and feces (trace amounts). The major biotransformation pathways were direct O-glucuronidation (44% of the dose), and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid, which was subsequently metabolized in parallel to 2-chlorophenyl glycine and 2-chlorobenzoic acid (mean percentage of the dose for the three acids together was 36%). Other routes were chiral inversion followed by O-glucuronidation (11%), and aromatic hydroxylation in combination with sulfate conjugation (5%). In plasma, unchanged drug accounted for 76.5% of the total radioactivity, with the R-enantiomer and the O-glucuronide of the parent drug as the only measurable plasma metabolites. With the use of very sensitive liquid chromatography-tandem mass spectrometry techniques, only traces of aromatic (pre)mercapturic acid conjugates were detected in urine (each <0.3% of the dose), suggesting a low potential for reactive metabolite formation. In conclusion, the disposition of RWJ-333369 in humans is characterized by virtually complete absorption, extensive metabolism, and unchanged drug as the only significant circulating species. (Rogawski, 2006). In preclinical studies (data on file), this drug has demonstrated broad anticonvulsant activity in acute rodent seizure models and in the kindled rat model of partial epilepsy. It has shown efficacy in attenuating the frequency of spontaneous recurrent seizures in the kainite post-status epilepticus rat model of temporal lobe epilepsy (Grabenstatter and Dudek, 2004) and suppressing spike and wave discharges in the GAERS (Genetic Absence Epilepsy Rat from Strasbourg) model of generalized absence epilepsy (Nehlig et al., 2005). Overall, the preclinical profile suggests that the drug will be useful in the treatment of epilepsy and other neurologic conditions where neurostabilization is desirable. RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-; CAS Registry Number 194085-75-1) is a new neuromodulator currently under clinical investigation for adjunctive treatment of epilepsyThe objective of the present study was to investigate the absorption, metabolism, and excretion of RWJ-333369 in humans and to identify and quantify its major and minor metabolites after a single oral dose of 500 mg of 14 C-RWJ-333369 to healthy male subjects. absorption, distribution, metabolism, and excretion characterization of RWJ-333369 in preclinical species and comparison ...

Metabolism and Excretion of RWJ-333369 [1,2-Ethanediol, 1-(2-Chlorophenyl)-, 2-carbamate, (S)-] in Mice, Rats, Rabbits, and Dogs

“…Trace amounts of M8 and M9 were observed in dog urine, and were quantifiable only by LC-MS/MS and not by radio-HPLC analysis (below the limit of quantitation of the radio-HPLC method, Ͻ0.3% of the dose). Similar to the dog, in human urine only trace amounts of M8 and M9 were detected by LC-MS/MS analyses (Mannens et al, 2007). Among the four animal species studied, the rabbit was unique in apparently not forming, to a significant extent, metabolites resulting from the oxidative pathways.…”

“…Similar to its metabolism in humans (Mannens et al, 2007), RWJ-333369 was extensively metabolized in all preclinical species; only dmd.aspetjournals.org minor amounts were excreted unchanged in urine and feces. Multiple metabolic pathways and renal excretion are involved in the elimination of RWJ-333369 and its metabolites.…”

“…In humans, only trace amounts of M21 were detected and the levels were below the limit of quantitation of the radio-HPLC method (Mannens et al, 2007). In plasma samples of rats and mice, a mixture of glucuronide conjugates of M4 and M5 (M12a,b) was present, but this was not seen in the dog and rabbit plasma.…”

“…Hence, parent RWJ-333369 was, in fact, the sum of the radioactive peaks of both RWJ-333369 and its degradation product X (R307716). Carbamoyl migration has been reported in human plasma samples (Mannens et al, 2007).…”

“…Approximately 10 aromatic MACs were synthesized and used as reference compounds for the purpose of cochromatographic comparison. The procedure for the synthesis of the 10 MACs and the HPLC separation data are described in Mannens et al (2007). pre-MACs of RWJ-333369 in rat urine were converted to MACs of RWJ-333369 and were cochromatographed with 10 different reference compounds of aromatic MACs of RWJ-333369.…”