Cebranopadol, a novel first-in-class drug candidate: Method validation and first exploratory pharmacokinetic study in rabbits

Cebranopadol is a novel, centrally acting, potent, first-in-class analgesic drug candidate with a unique mode of action that combines nociceptin/orphanin FQ peptide receptor and opioid peptide receptor agonism. The present study aimed to develop and validate a novel UHPLC-MS/MS method to quantify cebranopadol in rabbit plasma and to assess its pharmacokinetics in rabbits after subcutaneous (s.c.) administration. Twelve adult females were administered with 200 µg/kg s.c. injection. Blood samples were withdrawn at 15, 30 and 45 min and 1, 1.5, 2, 4, 6, 8, 10 and 24 hr after administration. The plasma samples were extracted with a liquid/liquid extraction. The new analytical method complied with the EMA requirements for the bioanalytical method validation. The method was selective, repeatable, accurate, precise and robust with a lower limit of quantification of 0.1 ng/ml. In all the rabbits, cebranopadol was quantifiable from 0.25 to 10 hr. Mean Cmax and Tmax were 871 ng/ml and 0.25 hr, respectively. Further studies including the i.v. administration are necessary to fully evaluate the pharmacokinetic features of this novel active compound

Development of a multimatrix UHPLC-MS/MS method for the determination of paracetamol and its metabolites in animal tissues

Paracetamol/acetaminophen (APAP) is one of the most popular pharmacologically active substances used as an analgesic and antipyretic agent. The metabolism of this drug occurs in the liver and leads to the formation of two main metabolites—glucuronic acid and sulfate derivate. Despite the wide use of paracetamol in veterinary medicine, a handful of analytical methods were published for the determination of paracetamol residues in animal tissues. In this paper, a multimatrix method has been developed for the determination of paracetamol and two metabolites—paracetamol sulfate (PS) and p-Acetamidophenyl β-D-glucuronide (PG). A validation procedure was conducted to verify method reliability and fit purpose as a tool for analyzing acetaminophen and metabolites in muscle, liver, lung, and kidney samples from different species of animals. Established validation parameters were in agreement with acceptable criteria laid by the European legislation. The initial significant matrix effect was successfully reduced by implementing an internal standard—4-Acetamidophenyl β-D-glucuronide-d3 (PG-d3, IS). The usefulness of the developed method was verified by analyzing samples from an experiment in which paracetamol was administrated to geese

Propacetamol in dogs: First description of its pharmacokinetics after intravenous and oral administration

Propacetamol is a prodrug form of paracetamol (APAP) licensed for human use as a pain reliever in postoperative care. It is prescribed if APAP cannot be administered orally or rectally to a patient and for patients in whom nonsteroidal anti-inflammatory drugs are contraindicated. In this study, we aimed to quantify the pharmacokinetics of APAP and its metabolites, paracetamol sulfate (PS), paracetamol glucuronide (PG), and N-acetyl-p-benzoquinone imine (NAPQI), after a single oral and intravenous (IV) administration of 30 mg/kg of propacetamol to six healthy adult Labrador dogs according to a 2 × 2 crossover study. The analyses were performed using a validated HPLC-MS/MS method. PS and PG exposures were higher than that of APAP, while NAPQI concentrations were constantly below the detection limit of the analytical method. IV propacetamol administration produced 30% more APAP than oral administration. However, propacetamol released a significantly lower amount of active moiety in dogs than in humans. The propacetamol dose administered in this study did not produce plasma APAP concentrations above the threshold sufficient to provide analgesia in adult humans (4 μg/mL). In conclusion, direct IV injection of APAP instead of propacetamol might be a better clinical option for pain relief in dogs