Sviluppo e validazione di un metodo HPLC per la determinazione della flupirtina nel plasma. Analisi farmacocinetica nei cani e nei gatti.
Bibliographic record
Abstract
Riassunto La flupirtina (FLU) è un farmaco analgesico non-oppioide appartenente alla classe del N-metil D-aspartato (NMDA) priva di proprietà antipiretiche e antiflogistiche, utilizzata nel trattamento di una vasta gamma di stati di dolore nell'uomo Lo scopo di questo studio è stato: • Sviluppare e validare un metodo analitico per la determinazione della FLU con HPLC-FL • Determinare il profilo farmacocinetico della FLU nei cani e nei gatti sani dopo differenti vie di somministrazioni e formulazioni Determinazione e validazione del metodo analitico Il metodo analitico descritto è risultato essere accurato e selettivo per la determinazione della FLU attraverso HPLC-FL. È stata utilizzata una fase mobile ACN:AcONH4 (20 mM) pH 6.8 (60:40, v/v) con un flusso di 1 mL/min in condizione isocratica e λ di emissione ed eccitazione rispettivamente di 370 e 323 nm. I tempi di ritenzione per la FLU e IS (trazodone) sono stati rispettivamente 4.6 ± 0.2 e 5.8 ± 0.2 min. La FLU ed il suo IS sono stati inoltre caratterizzati da un recupero rispettivamente del 75% e 67%. La determinazione del metodo è stata validata in accordo con le linee guida internazionali EMA. Il LOQ e LOD sono stati rispettivamente di 10 e 3 ng/mL. L’applicabilità di questo metodo è stata verificata attraverso la determinazione della FLU in plasma canino dopo singolo trattamento orale di Efiret® 5 mg/Kg. Sperimentazione animale Animali: sei cani adulti di razza Labrador e sei gatti adulti di razza mista sono stati utilizzati in due differenti sperimentazioni per valutare il profilo farmacocinetico della FLU. Cani: Una singola dose di farmaco è stata somministrata secondo un disegno a cross over (quadrato latino 4x4) attraverso quattro trattamenti (intravena IV, orale a rilascio immediato POIR, rettale RC 5 mg/kg FLU e orale a rilascio prolungato POPR 200mg/cane) a quattro diversi gruppi. Gatti: Una singola dose di farmaco è stata somministrata secondo un disegno a cross-over (quadrato latino 2X2) a due gruppi di animali utilizzando due diversi trattamenti (IV e PO 5 mg/Kg). Abstract Flupirtine (FLU) is a non-opiod analgesic drug belonging to the class of N-methyl-D-aspartate (NMDA). Its properties are used in the treatment of a wide range of pain states in humans without antipyretic or antiphlogistic effects. According to the literature, there is a substantial body of evidence on the efficacy of FLU in humans but no study has been performed in pets. The aim of this study was: • to determine and validate a bioanalytical method to detect FLU with HPLC-FL • to evaluate the pharmacokinetic profiles of FLU in healthy dogs and cats after different routes and formulations. Determination and validation of a bioanalytical method The analytical method provided a selective and accurate quantization of FLU through a HPLC-FL. The mobile phase consisted of ACN:AcONH4 (20 mM) pH 6.8 (60:40, v/v) at a flow rate of 1 mL/min in isocratic mode. Excitation and emission wavelengths were set at 323 and 370 nm, respectively. The recoveries of FLU and IS (trazodone) were about 75% and 67%. Typical retention times for FLU and IS were 4.6 ± 0.2 and 5.8 ± 0.2 min, respectively. The described method was validated according to international guidelines on the bioanalytical method validation. Limits of quantification and detection were 10 and 3 ng/mL, respectively. The applicability of this method has been verified by determining FLU in canine plasma after single oral treatment with 5 mg/kg of Efiret®. Animal and experimental design Animals: Six healthy Labrador breed adult dogs and six healthy mixed breed adult cats were used in two different experiments to evaluate the pharmacokinetic profiles (PK) of FLU. Study design: Dogs: single-dose, four-group and four-treatment (intravenous IV, oral immediate release POIR, per rectum RC routes 5 mg/kg FLU, oral prolonged release POPR route 200 mg/subject), crossover design (4x4 Latin-square). Cats: single-dose, two-group, two-treatment (IV and PO routes 5 mg/kg), crossover design (2x2 Latin-square). The wash out period was 1-week between trials. Blood samples were collected at assigned times and plasma was then analysed by the validated HPLC method. Some adverse effects were noted only in dogs of the IV group, however they resolved rapidly and spontaneously. In all the other groups, no adverse effects were observed. The FLU plasma concentrations were detectable in all groups up to 36 h following treatment. The bioavailability (F%) values after POIR, POPR and RC in dogs were 41.9, 36.8 and 29.3% respectively, while the PO F% in cats was 39.3 ± 9.7%. The PO F% in both dogs and cats was similar, but about two times smaller than that found in humans (90%). This large differences in F% demonstrated that PK values derived in dogs or in cats should not be extrapolated to humans, and vice versa. Conclusion: This study represents the first step that should pave the way for use of this active ingredient in veterinary field.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".