The absorption, metabolism, and excretion of the novel neuromodulator RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-) in humans.
RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-; CAS Registry Number 194085-75-1) is a novel neuromodulator in 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.
Mannens
G S J
GS
Department of Preclinical Pharmacokinetics, Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium. gmannens@prdbe.jnj.com
Hendrickx
J
J
Janssen
C G M
CG
Chien
S
S
Van Hoof
B
B
Verhaeghe
T
T
Kao
M
M
Kelley
M F
MF
Goris
I
I
Bockx
M
M
Verreet
B
B
Bialer
M
M
Meuldermans
W
W
D000284:Administration, Oral; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001711:Biotransformation; D002219:Carbamates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007408:Intestinal Absorption; D007668:Kidney / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D010084:Oxidation-Reduction; D012016:Reference Values; D013463:Sulfuric Acid Esters / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
D000927:Anticonvulsants; D002219:Carbamates; D020719:Glucuronides; C518914:S-2-O-carbamoyl-1-o-chlorophenyl-ethanol; D013463:Sulfuric Acid Esters; D014535:Uridine Diphosphate Glucuronic Acid