Probaly insignificant hepatic exposure. Palperidone is essentially eliminated without Cyp-participation. In spite of a molecular structure with potential risk for Cyp TDI, there is no significant capacity for Cyp-inhibition or Cyp-induction in clinical use. Even if increased appetite may be a bye- effects, the common gastrointestinal side effects motivate attention to the nutrition of the patient.

Benzioxazol piperidine pyridopyrimidine. The active metabolite of risperidone.

Indications: Schizophrenia. Manic symptoms in schizoaffective syndrome. Selective blocker of monoamine effects by binding to serotonergic 5HT2- and dopaminergic D2- receptors. It also blocks alpha1-adrenergic receptors. Peroral tabl: 3-12 mg/d. Depot injection:Starting dose 150 mg followed by further 100 mg one week later, after that 75 mg/month. About 70 % of the patients show increase in plasma prolactin levels. Increased secretion of prolactin is potentially anti-porphyrogenic through the inhibitory effect on FSH- induced progesterone-release. Common bye-effects are increased appetite and dose-related weight gain. Increased appetite, weight gain with increased plasma levels of triglycerides, LDL-cholesterol and glucose are common in treatment with atypical antipsychotics, and are the cardinal features of the metabolic syndrome. Increased appetite and weight gain with abdominal adiposity connected with the pre-diabetic and pre-atherosclerotic metabolic syndrome, is characterized by insulin resistance, hyperinsulinemia, hyperglycemia, cortisolemia and increased triglyceride and cholesterol levels. This is also observed in first episode psychoses prior to pharmacotherapy, indicating a mixed origin (PMID 18370698). Excess fatty acid is implicated in the pathogenesis of insulin resistance (PMID 18154189). The origin of the metabolic syndrome may thus be found in drug- or cortisol-induced increase in appetite - augmented food intake - chylomicronemia - augmented triglyceride hydrolysis in preportal fatty tissue via insulin-stimulated tissue lipoprotein lipase - strongly increased fatty acid (FA) traffic through the liver -increased hepatic VLDL formation - fatty liver - impaired hepatic insulin extraction from blood - hyperinsulinemia - insulin resistance - hyperglycemia. The visceral adipose tissue is not only an energy depot but also an endocrine organ which produces a large number of bioactive molecules. In the setting of obesity, overproduction of pro-inflammatory and pro-thrombotic adipokines is associated with insulin resistance (PMID 21196255), and PXR-inhibitory effects through the activation of NF-kB. Fatty acid-activated peroxisome proliferators-activated receptor (PPAR) isotypes may play beneficiary roles in the metabolic syndrome (PMID 20932114), through PPARb/d augmenting hepatic FA oxidation in muscle, through fatty tissue PPARg faciliating uptake of FA, lipid and glucose as well as stimulating glucose oxidation, and through PPARa participating in FA beta and omega oxidation mainly in liver and heart and ameliorate insulin resistance. These effects are taken advantage of in the treatment of diabetes through use of PPAR agonists. In rodents, carbohydrate response element binding protein (ChREBP) activated by feeding or glucose, reduces metabolic syndrome obesity, fatty liver and glucose intolerance by way of inhibition of glycogenolytic genes and activation lipogenic genes converting excess carbohydrate into triglyceride rather than glycogen (PMID 20842602). Clusterin is a stress-response protein contributing to the protein cargo of HDL and involved in diverse biological processes including lipid transport and inflammation. Its expression is increased by glucose, and insulin-activated SREBP-1c plays a crucial role in its metabolic regulation (PMID 21549685). The concentration of clusterin in HDL is lower in conditions with low plasma HDL and high plasma triglyceride concentrations, the key lipid characteristics of the metabolic syndrome. HDL clusterin levels are also lower in individuals with higher body mass index and reduced insulin sensitivity (PMID 20847305). Confounding side effects: Common: Tachycardia, nausea, vomiting, dyspepsia, obtipation, upper abdominal pain, dorsal pain, extremity pain, arthalgia. Less common: Urinary retention, myalgia, insomnia.

Paliperidon is not significantly metabolized in the liver, a larger part of the dose being excreted unchanged in urine. There is no in vivo evidence for Cyp 3A4 or 2D6 metabolism, and no indications for capacity of affecting the disposal of drugs metabolized by Cyps 1A2, 2A6, 2C8/9/10, 2D6, 2E1, 3A4 or 3A5.