Absorption, Metabolism, and Excretion of Paliperidone, a New Monoaminergic Antagonist, in Humans
Abstract
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.
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Paliperidone is primarily renally cleared and not extensively metabolized in the liver; 59% of a single dose is excreted in the urine unchanged.
“Paliperidone is primarily renally cleared and not extensively metabolized in the liver; 59% of a single dose is excreted in the urine unchanged [43, 77].”
From Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview (2021) · cites this paper as [43]
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“On average, each of these metabolites accounts for less than 5% of total excretion; approximately 60% of PAL is excreted directly from the kidneys (Vermeir et al. 2008).”
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BackgroundPharmacokinetics and tolerability of paliperidone palmitate injection in Chinese subjects
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“Other than renal excretion, four metabolic pathways were involved in the elimination of paliperidone, including CYP3A4 and CYP2D6 enzymes, each of which accounted for up to 6.5% of the administered dose (Vermeir et al., 2008).”
BackgroundInfluentialWong, Y. C., Centanni, M., & de Lange, E. C. M. (2019) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.1365 · Cited by 18 · see citing works
Jadhav, S. A., Landge, S. B., Choudhari, P. M., Solanki, P. V., Bembalkar, S. R., & Mathad, V. T. (2011) · Chromatography Research International · doi:10.4061/2011/256812 · Cited by 18 · see citing works
Remmerie, B. M. M., Ariyawansa, J., Meulder, M. D., Coppola, D., & Berwaerts, J. (2015) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.648 · Cited by 17 · see citing works
Self-citationAmatniek, J. C., Canuso, C. M., Deutsch, S. I., Henderson, D. C., Mao, L., Mikesell, C., Rodriguez, S., Sheehan, J. J., & Alphs, L. D. (2013) · Clinical Schizophrenia & Related Psychoses · doi:10.3371/csrp.amca.021513 · Cited by 17 · see citing works
Paliperidone palmitate injection for the acute and maintenance treatment of schizophrenia in adults
Bishop, J. R., Kim, Solari, & Weiden, P. J. (2012) · Patient Preference and Adherence · doi:10.2147/ppa.s20657 · Cited by 17 · see citing works
“5 In vitro studies in human liver microsomes revealed that paliperidone palmitate does not appreciably inhibit the metabolism of drugs metabolized by cytochrome P450 (CYP) isozymes and is not significantly metabolized by CYP1A2, CYP2A6, CPY2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CPY3A5.”
InfluentialZhang, T., Yang, Y., Zhao, X., Jia, J., Su, H., He, H., Gu, J., & Zhu, G. (2014) · CrystEngComm · doi:10.1039/c4ce00784k · Cited by 17 · see citing works
Spina, E., & Crupi, R. (2011) · Journal of Central Nervous System Disease · doi:10.4137/jcnsd.s1607 · Cited by 17 · see citing works
Single‐dose pharmacokinetics of paliperidone extended‐release tablets in healthy Chinese subjects
Si, T., Shu, L., Liu, Y., Su, Y., Chunmei, G., & Hongyan, Z. (2010) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.1132 · Cited by 16 · see citing works
“There is no relationship between the genotypic expression of metabolizing enzymes UGT1A1 and UGT1A6 and paliperidone pharmacokinetics(Vermeir et al., 2008).”
Yang, L. P. H. (2011) · CNS Drugs · doi:10.2165/11207440-000000000-00000 · Cited by 16 · see citing works
Xiamuxi, H., Wang, Z., Li, J., Wang, Y., Wu, C., Yang, F., Jiang, X., Liu, Y., Zhao, Q., Chen, W., et al. (2017) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2017.07.040 · Cited by 16 · see citing works
Schoretsanitis, G., Meyer, J. M., Conca, A., & Hiemke, C. (2023) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2023.2220962 · Cited by 15 · see citing works
“Oral paliperidone undergoes hepatic metabolism to a limited extend with one-fourth being catalyzed by CYP3A4; the rest is eliminated unchanged in urine [76].”
BackgroundInfluence of CYP2C19 and CYP2D6 on side effects of aripiprazole and risperidone: A systematic review
Brabander, E. Y. D., Schaars, K. K., van Amelsvoort, T., Budde, M., Heilbronner, U., Young, A. H., Juruena, M. F., Vieta, E., Fares‐Otero, N. E., Kas, M. J., et al. (2024) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2024.04.001 · Cited by 15 · see citing works
Taylor, K., & Elliott, S. P. (2013) · Drug Testing and Analysis · doi:10.1002/dta.1503 · Cited by 15 · see citing works
Baumann, P., & Hiemke, C. (2012) · doi:10.1002/9783527630905.ch11 · Cited by 15 · see citing works
Peuskens, J., Rubio, G., & Schreiner, A. (2014) · Annals of General Psychiatry · doi:10.1186/1744-859x-13-10 · Cited by 14 · see citing works
“Paliperidone ER is not expected to cause clinically important hepatic PK interactions with drugs that are metabolized by cytochrome P450 isozymes [75].”
BackgroundCanuso, C. M., & Battisti, W. P. (2010) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2010.495387 · Cited by 14 · see citing works
“Unlike risperidone and several other atypical antipsychotics, CYP2D6 and CYP3A4 isozymes seem to be minimally involved with paliperidone’s metabolism [25].”
BackgroundClinically Important Differences in the Pharmacokinetics of the Ten Newer “Atypical” Antipsychotics
Preskorn, S. (2012) · Journal of Psychiatric Practice · doi:10.1097/01.pra.0000419820.68128.ad · Cited by 14 · see citing works
Suzuki, H., Gen, K., Otomo, M., Inoue, Y., Hibino, H., Mikami, A. S., Matsumoto, H., & Mikami, K. (2014) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.2393 · Cited by 14 · see citing works
“PAL is considered to be less affected by individual differences in metabolism than risperidone and to have less risk for interactions with other drugs (Vermeir et al., 2008).”
BackgroundMicrobial impacts in postmortem toxicology
Castle, J. W., Butzbach, D. M., Walker, G., Lenehan, C. E., Reith, F., & Kirkbride, K. P. (2017) · doi:10.1002/9781119062585.ch9 · Cited by 14 · see citing works
Suzuki, H., Gen, K., Otomo, M., Inoue, Y., Hibino, H., Mikami, A. S., Matsumoto, H., & Mikami, K. (2013) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12026 · Cited by 13 · see citing works
“It is thought that PAL is less likely to be affected by inter-individual differences in metabolism than risperidone, and to present less risk of drug–drug interactions.(3) The creation of an osmotic pump extended-release formulation that continually releases the drug at a constant rate over a period of 24 h, moreover,…”
BackgroundMahdy, W. Y. B., Yamamoto, K., Ito, T., Fujiwara, N., Fujioka, K., Horai, T., Otsuka, I., Imafuku, H., Omura, T., Iijima, K., et al. (2023) · Clinical and Translational Science · doi:10.1111/cts.13473 · Cited by 12 · see citing works
Krishna, M. V., Nellutla, A., Gorrepati, M., Majeti, S., & Mamidala, S. K. (2015) · Annales Pharmaceutiques Françaises · doi:10.1016/j.pharma.2015.04.002 · Cited by 12 · see citing works
Rub, R. A., Beg, S., Kazmi, I. A., Afzal, O., Almalki, W. H., Alghamdi, S. A., Akhter, S., Ali, A., & Ahmed, F. J. (2020) · Journal of Chromatography B · doi:10.1016/j.jchromb.2020.122433 · Cited by 12 · see citing works
Boyda, H. N., Procyshyn, R. M., Tse, L., Yuen, J. W. Y., Honer, W. G., & Barr, A. M. (2021) · PLoS ONE · doi:10.1371/journal.pone.0246211 · Cited by 12 · see citing works
“Paliperidone, by contrast, is predominantly excreted unchanged in the urine [91].”
BackgroundJudson, P. N., Long, A., Murray, E. J., & Patel, M. L. (2015) · Molecular Informatics · doi:10.1002/minf.201400184 · Cited by 11 · see citing works
Pharmacokinetic drug evaluation of paliperidone in the treatment of schizoaffective disorder
Macaluso, M., Oliver, H., & Sohail, Z. (2017) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2017.1351546 · Cited by 11 · see citing works
Chen, H., Zhao, L., Li, G., Leng, D., Ma, P., Lijin, T., & Zhang, T. (2014) · Asian Journal of Pharmaceutical Sciences · doi:10.1016/j.ajps.2014.07.008 · Cited by 11 · see citing works
Escitalopram-induced liver injury: A case report and review of literature
Ng, Q. X., Yong, C. S. K., Loke, W., Yeo, W. S., & Soh, A. Y. S. (2019) · World Journal of Hepatology · doi:10.4254/wjh.v11.i10.719 · Cited by 11 · see citing works
Schoretsanitis, G., Haen, E., Conca, A., Piacentino, D., Ridders, F., Hiemke, C., Gründer, G., & Paulzen, M. (2020) · Pharmacopsychiatry · doi:10.1055/a-1221-5293 · Cited by 9 · see citing works
“5 % of the absorbed paliperidone [27, 40], and most of it is excreted unchanged [25].”
BackgroundPaliperidone in the treatment of delirium: results of a prospective open-label pilot trial
Yoon, H.-K., Kim, Y., Han, C., Ko, Y., Lee, H., Kwon, D., & Kim, L. (2011) · Acta Neuropsychiatrica · doi:10.1111/j.1601-5215.2011.00568.x · Cited by 9 · see citing works
“About half of the renal excretion occurred by active secretion (27).”
BackgroundPaliperidone for the Treatment of Ketamine-Induced Psychosis: A Case Report
Zuccoli, M. L., Muscella, A., Fucile, C., Carrozzino, R., Mattioli, F., Martelli, A., & Orengo, S. (2014) · The International Journal of Psychiatry in Medicine · doi:10.2190/pm.48.2.c · Cited by 9 · see citing works
“In vitro studies showed that paliperidone is mostly excreted unchanged in urine, being for only a very small fraction metabolized by two isozymes, CYP 2D6 and 3A4 [18].”
BackgroundSawant, S. D., & Barge, V. (2013) · Journal of Pharmacy Research · doi:10.1016/j.jopr.2012.11.011 · Cited by 9 · see citing works
Paliperidone Induced Hypoglycemia by Increasing Insulin Secretion
Omi, T., Riku, K., Fukumoto, M., Kanai, K., Omura, Y., Takada, H., & Matunaga, H. (2016) · Case Reports in Psychiatry · doi:10.1155/2016/1805414 · Cited by 9 · see citing works
Identification of postmortem paliperidone metabolite in human blood by LC–Q-Orbitrap-MS
Yamagishi, Y., Inokuchi, G., Hoshioka, Y., Nagasawa, S., Iwase, H., & Ogra, Y. (2023) · Journal of Analytical Toxicology · doi:10.1093/jat/bkad033 · Cited by 9 · see citing works
Božina, N., Jovanović, N., Lovrić, M., & Medved, V. (2008) · Therapeutic Drug Monitoring · doi:10.1097/ftd.0b013e3181896afc · Cited by 9 · see citing works
“Its active metabolite 9-hydroxyrisperidone (9-OHrisperidone) is approximately equipotent with the parent drug in dopamine receptor affinity and has been recently approved as the new antipsychotic drug called paliperidone.(2) The entire risperidone active moiety (risperidone plus 9-OH-risperidone) is regarded to contri…”
BackgroundFagiolini, A. M., Casamassima, F., Mostacciuolo, W., Forgione, R. N., Goracci, A., & Goldstein, B. I. (2010) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2010.490831 · Cited by 9 · see citing works
“Paliperidone is excreted unchanged through kidneys with minimal hepatic metabolism [86].”
BackgroundRussu, A., Savitz, A., Mathews, M., Gopal, S., Feng, Y., & Samtani, M. N. (2019) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000001137 · Cited by 8 · see citing works
“Following administration of a single oral dose of 1 mg immediate-release (IR) (14)C-paliperidone, 59% of the dosewas excreted unchanged into urinewithin 1week, indicating that paliperidone is not extensively metabolized in the liver.(14) Approximately 80% of the administered radioactivity was recovered in urine and 11…”
BackgroundZhao, J., Cai, S., Lu, H., Bai, Z., & Wu, R. (2015) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s84833 · Cited by 8 · see citing works
“Paliperidone ER is less prone to hepatic drug-drug interactions due to the lack of cytochrome P450 inhibition and less hepatic metabolism.(9) As a result, there is only a small reduction in total exposure to paliperidone ER in patients with hepatic impairment.”
Systemic Inflammation Complicates the Interpretation of Therapeutic Drug Monitoring of Risperidone
Helland, A., Habib, S., Ulvestad, L., & Spigset, O. (2018) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000000873 · Cited by 8 · see citing works
- Authors
- Vermeir, M., Naessens, I., Remmerie, B., Mannens, G., Hendrickx, J., Sterkens, P., Talluri, K., Boom, S., Eerdekens, M., van Osselaer, N., & Cleton, A.
- Affiliations
- Janssen (Belgium) (BE)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2008-04
- Volume
- 36
- Issue
- 4
- Pages
- 769-779
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W2127872656
- Cited by
- 158
- References
- 16
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 8 · 2022: 5 · 2021: 7 · 2020: 4 · 2019: 10 · 2018: 9 · 2017: 10 · 2016: 9 · 2015: 8 · 2014: 13 · 2013: 16 · 2012: 14
- FWCI
- 10.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
- Keywords
- paliperidone, pharmacokinetics, drug metabolism, renal excretion, atypical antipsychotics, CYP2D6 polymorphism, N-dealkylation, glucuronidation, metabolites
- MeSH terms
- Paliperidone Palmitate, Adult, Feces, Humans, Intestinal Absorption, Isoxazoles, Kidney, Liver, Male, Middle Aged, Pyrimidines, Time Factors, Biogenic Monoamines, Metabolic Networks and Pathways
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