Absorption, metabolism, and excretion of paliperidone, a new monoaminergic antagonist, in humans.
Absorption, metabolism, and excretion of paliperidone, an atypical antipsychotic, was studied in five healthy male subjects after a single dose of 1 mg of [(14)C]paliperidone oral solution ( approximately 16 microCi/subject). One week after dosing, 88.4 to 93.8% (mean 91.1%) of the administered radioactivity was excreted: 77.1 to 87.1% (mean 79.6%) in urine and 6.8 to 14.4% (mean 11.4%) in the feces. Paliperidone was the major circulating compound (97% of the area under the plasma concentration-time curve at 24 h). No metabolites could be detected in plasma. Renal excretion was the major route of elimination with 59% of the dose excreted unchanged in urine. About half of the renal excretion occurred by active secretion. Unchanged drug was not detected in feces. Four metabolic pathways were identified as being involved in the elimination of paliperidone, each of which accounted for up to a maximum of 6.5% of the biotransformation of the total dose. Biotransformation of the drug occurred through oxidative N-dealkylation (formation of the acid metabolite M1), monohydroxylation of the alicyclic ring (M9), alcohol dehydrogenation (formation of the ketone metabolite M12), and benzisoxazole scission (formation of M11), the latter in combination with glucuronidation (M16) or alicyclic hydroxylation (M10). Unchanged drug, M1, M9, M12, and M16 were detected in urine; M10 and M11 were detected in feces. The monohydroxylated metabolite M9 was solely present in urine samples of extensive CYP2D6 metabolizers, whereas M10, another metabolite monohydroxylated at the alicyclic ring system, was present in feces of poor metabolizers as well. In conclusion, paliperidone is not metabolized extensively and is primarily renally excreted.
Vermeir
Marc
M
Johnson & Johnson Pharmaceutical Research and Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. mvermeir@prdbe.jnj.com
Naessens
Ineke
I
Remmerie
Bart
B
Mannens
Geert
G
Hendrickx
Jan
J
Sterkens
Patrick
P
Talluri
Krishna
K
Boom
Sandra
S
Eerdekens
Marielle
M
van Osselaer
Nancy
N
Cleton
Adriaan
A
D000328:Adult; D015306:Biogenic Monoamines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007555:Isoxazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors
D015306:Biogenic Monoamines; D007555:Isoxazoles; D011743:Pyrimidines; D000068882:Paliperidone Palmitate