Metabolism of Paliperidone (Invega)
Primary Metabolic Pathway
- Paliperidone undergoes minimal hepatic metabolism with renal excretion being the major route of elimination. 1
- Paliperidone is the active metabolite of risperidone (9-hydroxyrisperidone), but has a distinctly different metabolic profile from its parent compound 2, 3
- Unlike many antipsychotics, paliperidone is not extensively metabolized by the cytochrome P450 (CYP) enzyme system 1, 4
Limited Hepatic Metabolism
- Paliperidone has four minor metabolic pathways, but these represent only a small fraction of its total body clearance 3
- In vitro studies have shown that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, but in vivo studies do not show significant elimination by these isozymes 1
- Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19 enzymes 1
- P-glycoprotein (P-gp) has been identified as a transporter for paliperidone, with paliperidone being a P-gp substrate 1, 5
Excretion Profile
- Renal excretion is the predominant elimination pathway for paliperidone, with approximately 59% of the dose excreted unchanged in urine 2, 3
- The terminal elimination half-life of paliperidone is approximately 23 hours 2
- Pharmacokinetics are dose-proportional within the recommended dose range 2
Clinical Implications of Metabolic Profile
- Being a CYP2D6 poor metabolizer is not clinically relevant for paliperidone treatment, unlike with risperidone therapy 3
- Paliperidone has a lower potential for drug-drug interactions compared to many other antipsychotics due to its limited hepatic metabolism 5
- Dose adjustment is necessary in patients with renal impairment since renal excretion is the major elimination pathway 1, 5
Drug Interactions
- Paliperidone does not substantially inhibit drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 1
- Strong CYP3A4 and P-gp inducers like carbamazepine can decrease paliperidone plasma concentrations by approximately 37% through increased renal clearance 1
- Valproate coadministration may increase paliperidone exposure by approximately 50%, potentially requiring dose reduction 1
- Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations, but the clinical relevance is unknown 1
Comparison to Risperidone
- Unlike risperidone, which is extensively metabolized by CYP2D6 to form paliperidone, paliperidone itself undergoes minimal hepatic metabolism 3, 4
- Paliperidone may be preferred over risperidone when liver disease, drug-drug interactions, or other alterations in metabolism make appropriate dosing of risperidone difficult 2
- Paliperidone has decreased inhibition of P-glycoprotein compared to risperidone, further reducing potential for drug-drug interactions 5