V. De Vito

Pharmacokinetic profiles of the analgesic drug flupirtine in cats

Flupirtine (FLU) is a non-opioid analgesic drug with no antipyretic or antiphlogistic effects, used in the treatment of a wide range of pain states in human beings. There is a substantial body of evidence on the efficacy of FLU in humans but this is inadequate to recommend its off-label use in veterinary clinical practice. The aim of this study was to evaluate the pharmacokinetic profiles of FLU after IV and PO administration in healthy cats. Six mixed breed adult cats were randomly assigned to two treatment groups using an open, single-dose, two-treatment, two-phase, paired, cross-over design (2 × 2 Latin-square). Group 1 (n  =  3) received a single dose of 5 mg/kg of FLU injected IV into the jugular vein. Group 2 (n  =  3) received the same dose via PO route. The wash out period was 1 week. Blood samples (1 mL) were collected at assigned times and plasma was then analysed by a validated HPLC method. No adverse effects at the point of injection and no behavioural changes or alterations in health parameters were observed in the animals during or after the study (up to 7 days after the full study). After IV administration, FLU was detectable in plasma up to 36 h. After PO administration, FLU plasma concentrations were lower than those following IV administration, but they were detectable over the same time range. The terminal part of both mean pharmacokinetic curves showed a similar trend of elimination. The oral bioavailability was approximately 40%. This is the first study of FLU in an animal species of veterinary interest and it could pave the way for the use of this active ingredient in the veterinary field.

Pharmacokinetics and disposition of flupirtine in the horse

Flupirtine (FLU) is a non-opioid analgesic drug, with no antipyretic or anti-inflammatory effects, used in the treatment of a wide range of pain states in human beings. It does not induce the side effects associated with the classical drugs used as pain relievers. The aim of this study was to evaluate the pharmacokinetic profiles of FLU after IV and PO administration in healthy horses. Six mixed breed adult mares were randomly assigned to two treatment groups using an open, single-dose, two-treatment, two-phase, paired, cross-over design (2 × 2 Latin-square). Group 1 (n = 3) received a single dose of 1 mg/kg of FLU injected IV into the jugular vein. Group 2 (n = 3) received FLU (5 mg/kg) via nasogastric tube. The animals then swapped groups after a 1-week wash-out period and the doses were repeated. Blood samples (5 mL) were collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 24, 36 and 48 h and plasma was then analysed by a validated HPLC method. Some mild and transient adverse effects (that spontaneously resolved within 5 min) were observed in 2/6 animals after IV administration. No adverse effects were noticed in the PO administration group. After IV and PO administrations, FLU was detectable in plasma for up to 36 h. The mean elimination half-life was longer after PO (10.27 h) than after IV (3.02 h) administration. The oral bioavailability was 71.4 ± 33.1%. After compartmental simulation/modelling, an oral dose of 2.6 mg/kg was calculated to give Cmax and AUC values in horses similar to those reported in humans after a clinical dose administration with a theoretical FLU effective plasma concentration of 187 ng/mL. These findings may form the basis for further studies concerning this active ingredient in equine medicine.

Pharmacokinetics of tapentadol in laying hens and its residues in eggs after multiple oral dose administration

ABSTRACT 1. The aim of the study was to evaluate the pharmacokinetics (PKs) of tapentadol (TAP), a novel opioid analgesic, in laying hens after intravenous (IV) and oral (PO) administration and to quantify the concentrations of TAP residues in eggs. 2. Twenty healthy laying hens were divided into three groups: A (n = 6), B (n = 6) and C (n = 8). The study was conducted in two phases. Groups A and B received TAP by IV and PO routes at the dose of 1 and 5 mg/kg, respectively. 3. No visible adverse effects were observed after administration of the drug. TAP plasma concentrations were detectable up to 4 h following administration. Following IV administration, TAP plasma concentrations were only higher than the minimal effective concentration (148 ng/ml) reported for humans for 1 h. After single PO administration, plasma concentrations of TAP would not conform to software algorithms and the PK parameters were not calculated. TAP concentration following multiple PO doses at 5 mg/kg for 5 d was found to be higher and more persistent (12 h vs. 7 h) in yolk compared with albumen. 4. This is the first PK study on the novel atypical opioid TAP in laying hens. Further studies are required to investigate the analgesic efficacy and actual effective plasma concentration of TAP in this species.

Efficacy of florfenicol and gamithromycin in an Ornithobacterium rhinotracheale infection model in turkeys: a pharmacokinetic-pharmacodynamic approach

Introduction: The anatomy and physiology of pigs is closely related to human characteristics. Therefore, the use of pigs as an animal model to study the pharmacokinetic (PK) behavior of drugs in therapeutic subpopulations, including pediatrics, could be of interest. One of the key PK processes, biotransformation, is primarily mediated by the cytochrome P450 (CYP) enzyme system. Literature reports have demonstrated a high homology between human and porcine CYP3A, 2C and 2E in adults, namely at least 75, 62 and 79% amino acid sequence identity, respectively. However, data regarding the ontogeny of porcine CYP enzymes are lacking. Therefore, in order to assess whether piglets might serve as a model for pediatric PK studies, knowledge regarding the ontogeny of the CYP enzymes in pigs is mandatory. Materials and methods: Liver samples were collected immediately after euthanasia from 16 pigs (8 males and 8 females, Hybrid sow x Pietrain boar) of different ages (2 days, 4 and 8 weeks, 6 months-old). Samples were snap-frozen and stored at <-80°C until analysis. Microsomes were prepared by a differential centrifugation method. Midazolam, tolbutamide and chlorzoxazone probe drugs were used to determine the in vitro CYP3A, 2C and 2E catalytic activity, respectively. The corresponding metabolites, namely 1-hydroxy-midazolam, 4-hydroxy-tolbutamide and 6-hydroxy-chlorzoxazone, were quantified using a validated UHPLC-MS/MS method (1). Furthermore, the microsomal protein per gram of liver was determined as it is an important scaling factor in the extrapolation of the obtained in vitro enzyme activities to in vivo (2). Results and conclusions: The biotransformation of midazolam, tolbutamide and chlorzoxazone increased with age. The mean (±SD) CYP3A activity was 60.5 (±45.7) and 83.3 (±20.7) pmol/min/mg protein at the age of 2 days, 971.1 (±367.8) and 1072.7 (±371.7) pmol/min/mg protein at the age of 4 weeks and 723.4 (±146.3) and 1134.7 (±282.6) pmol/min/mg protein at 8 weeks of age for the barrows and sows, respectively. CYP2C activity at the same ages increased from 20.1 (±12.3) and 29.1 (±18.5) to 78.3 (±25.6) and 106.7 (±69.1) and 103.5 (±39.6) and 170.2 (±71.9) pmol/min/mg protein, while the activity of CYP2E was 539.3 (±251.0) and 643.3 (±220.3), 747.7 (±134.8) and 948.9 (±246.2) and 957.9 (±221.7) and 1549.8 (±345.0) pmol/min/mg protein, respectively for the barrows and sows. Significant sex differences (P<0.05) were only observed at 8 weeks of age. These data show similar trends with human CYP ontogeny.

Flupirtine: pharmacokinetics and disposition in the horse

Introduction: The anatomy and physiology of pigs is closely related to human characteristics. Therefore, the use of pigs as an animal model to study the pharmacokinetic (PK) behavior of drugs in therapeutic subpopulations, including pediatrics, could be of interest. One of the key PK processes, biotransformation, is primarily mediated by the cytochrome P450 (CYP) enzyme system. Literature reports have demonstrated a high homology between human and porcine CYP3A, 2C and 2E in adults, namely at least 75, 62 and 79% amino acid sequence identity, respectively. However, data regarding the ontogeny of porcine CYP enzymes are lacking. Therefore, in order to assess whether piglets might serve as a model for pediatric PK studies, knowledge regarding the ontogeny of the CYP enzymes in pigs is mandatory. Materials and methods: Liver samples were collected immediately after euthanasia from 16 pigs (8 males and 8 females, Hybrid sow x Pietrain boar) of different ages (2 days, 4 and 8 weeks, 6 months-old). Samples were snap-frozen and stored at <-80°C until analysis. Microsomes were prepared by a differential centrifugation method. Midazolam, tolbutamide and chlorzoxazone probe drugs were used to determine the in vitro CYP3A, 2C and 2E catalytic activity, respectively. The corresponding metabolites, namely 1-hydroxy-midazolam, 4-hydroxy-tolbutamide and 6-hydroxy-chlorzoxazone, were quantified using a validated UHPLC-MS/MS method (1). Furthermore, the microsomal protein per gram of liver was determined as it is an important scaling factor in the extrapolation of the obtained in vitro enzyme activities to in vivo (2). Results and conclusions: The biotransformation of midazolam, tolbutamide and chlorzoxazone increased with age. The mean (±SD) CYP3A activity was 60.5 (±45.7) and 83.3 (±20.7) pmol/min/mg protein at the age of 2 days, 971.1 (±367.8) and 1072.7 (±371.7) pmol/min/mg protein at the age of 4 weeks and 723.4 (±146.3) and 1134.7 (±282.6) pmol/min/mg protein at 8 weeks of age for the barrows and sows, respectively. CYP2C activity at the same ages increased from 20.1 (±12.3) and 29.1 (±18.5) to 78.3 (±25.6) and 106.7 (±69.1) and 103.5 (±39.6) and 170.2 (±71.9) pmol/min/mg protein, while the activity of CYP2E was 539.3 (±251.0) and 643.3 (±220.3), 747.7 (±134.8) and 948.9 (±246.2) and 957.9 (±221.7) and 1549.8 (±345.0) pmol/min/mg protein, respectively for the barrows and sows. Significant sex differences (P<0.05) were only observed at 8 weeks of age. These data show similar trends with human CYP ontogeny.

PK/PD evaluation of the novel atypical opioid tapentadol in yellow-bellied slider turtles (Trachemys scripta scripta)

Introduction: The anatomy and physiology of pigs is closely related to human characteristics. Therefore, the use of pigs as an animal model to study the pharmacokinetic (PK) behavior of drugs in therapeutic subpopulations, including pediatrics, could be of interest. One of the key PK processes, biotransformation, is primarily mediated by the cytochrome P450 (CYP) enzyme system. Literature reports have demonstrated a high homology between human and porcine CYP3A, 2C and 2E in adults, namely at least 75, 62 and 79% amino acid sequence identity, respectively. However, data regarding the ontogeny of porcine CYP enzymes are lacking. Therefore, in order to assess whether piglets might serve as a model for pediatric PK studies, knowledge regarding the ontogeny of the CYP enzymes in pigs is mandatory. Materials and methods: Liver samples were collected immediately after euthanasia from 16 pigs (8 males and 8 females, Hybrid sow x Pietrain boar) of different ages (2 days, 4 and 8 weeks, 6 months-old). Samples were snap-frozen and stored at <-80°C until analysis. Microsomes were prepared by a differential centrifugation method. Midazolam, tolbutamide and chlorzoxazone probe drugs were used to determine the in vitro CYP3A, 2C and 2E catalytic activity, respectively. The corresponding metabolites, namely 1-hydroxy-midazolam, 4-hydroxy-tolbutamide and 6-hydroxy-chlorzoxazone, were quantified using a validated UHPLC-MS/MS method (1). Furthermore, the microsomal protein per gram of liver was determined as it is an important scaling factor in the extrapolation of the obtained in vitro enzyme activities to in vivo (2). Results and conclusions: The biotransformation of midazolam, tolbutamide and chlorzoxazone increased with age. The mean (±SD) CYP3A activity was 60.5 (±45.7) and 83.3 (±20.7) pmol/min/mg protein at the age of 2 days, 971.1 (±367.8) and 1072.7 (±371.7) pmol/min/mg protein at the age of 4 weeks and 723.4 (±146.3) and 1134.7 (±282.6) pmol/min/mg protein at 8 weeks of age for the barrows and sows, respectively. CYP2C activity at the same ages increased from 20.1 (±12.3) and 29.1 (±18.5) to 78.3 (±25.6) and 106.7 (±69.1) and 103.5 (±39.6) and 170.2 (±71.9) pmol/min/mg protein, while the activity of CYP2E was 539.3 (±251.0) and 643.3 (±220.3), 747.7 (±134.8) and 948.9 (±246.2) and 957.9 (±221.7) and 1549.8 (±345.0) pmol/min/mg protein, respectively for the barrows and sows. Significant sex differences (P<0.05) were only observed at 8 weeks of age. These data show similar trends with human CYP ontogeny.