The influence of modulation of P-glycoprotein and /or cytochrome P450 3A on the pharmacokinetics and pharmacodynamics of orally administered morphine in dogs

The influence of pretreatment with ketoconazole [cytochrome P450 3A (CYP3A) + P-glycoprotein (P-gp) inhibitor], elacridar (selective P-gp inhibitor) and rifampicin (CYP3A + P-gp inducer) on oral morphine pharmacokinetics and pharmacodynamics was investigated in experimental dogs. Seven beagles were used in a four-way crossover design. Morphine hydrochloride was administered orally (2.5 mg/kg) alone (control group CON) or after pretreatment with ketoconazole (group KETO), elacridar (group ELA) or rifampicin (group RIF). Morphine plasma concentrations were analysed by liquid chromatography-tandem mass spectrometry. Sedation scores (none, mild, moderate or severe) were evaluated subjectively. Dogs were significantly (P < 0.05) more sedated after ketoconazole pretreatment. There were no significant differences between group CON and the other pretreatment groups in pharmacokinetic parameters taking both sexes into account. Sex differences were apparent in some pharmacokinetic parameters of morphine. The area under the plasma concentration time curve (AUC(0-∞) ) was significantly higher, and the total body clearance was significantly lower in male compared to female dogs in all treatment groups. Ketoconazole, rifampicin and elacridar pretreatment had no significant effects on morphine pharmacokinetics, although dogs in the ketoconazole group showed higher sedation scores.     

Species comparison of enantioselective oral bioavailability and pharmacokinetics of ketoprofen

As a part of ongoing research to further elucidate frequent and species-specific causes of differences in oral bioavailability, a 3 mg/kg dose of racemic ketoprofen, a high permeability/low solubility compound in the human biopharmaceutics classification system, was administered intravenously and orally to different species. Due to possible enantioselective disposition kinetics and inversion, enantiomers were quantitated separately using a stereospecific HPLC assay. The absolute bioavailability of R(−) and S(+) ketoprofen in chickens, turkeys, dogs and pigs was 31.5% and 52.6%, 42.6% and 32.5%, 33.6% and 89.1%, and 85.9% and 83.5% respectively. Incomplete bioavailability in poultry is probably due to incomplete absorption in addition to first-pass elimination. Low bioavailability of R(−) ketoprofen in dogs, strongly indicates first-pass metabolism. High bioavailability of S(+) ketoprofen in dogs and both enantiomers in pigs confirms that absorption of these substances is complete and controlled by gastric emptying rather than dissolution.     

Pharmacokinetics of a lidocaine patch 5% in dogs

Lidocaine is increasingly used in transdermal drug delivery systems for different pain conditions in human medicine whereby several pharmacokinetic studies have demonstrated minimal systemic absorption in men. In the present study, the pharmacokinetics of a lidocaine patch 5% was studied in six dogs. In the first experiment, one single lidocaine patch was applied for 12 h to the lateral side of the thorax after removing the hair either by clipping or by the application of a depilatory agent, according to a two-way crossover design. No potential adverse effects induced by the patches were observed in either group. In dogs with clipped hair, a mean peak plasma lidocaine concentration of 62.94 ng/ml was obtained after 10.67 h. In the depilatory group, a mean peak plasma concentration of 103.55 ng/ml was reached after 9.27 h. Significant differences in the AUC(0 --> infinity), C(max), k(a) and T(1/2a) were noticed between the two groups. No significant differences were found for the elimination parameters and for T(max). In the second experiment, the patches were applied for 60 h to the clipped skin in order to study the absorption kinetics after a prolonged application period. There, the mean peak lidocaine plasma concentration was 45.18 ng/ml achieved after 24 h and a final concentration of 29.37 ng/ml was obtained at 60 h. In conclusion, all dogs tolerated the transdermal lidocaine patch well. The results of this study suggest that there is an overall minimal absorption from the lidocaine patch. However, the application of a depilatory agent leads to a more rapid and increased absorption of lidocaine.     

Intravenous amiodarone treatment in horses with chronic atrial fibrillation

Six horses without underlying cardiac disease were presented because of atrial fibrillation of between 5 and 12 months duration. These horses received an intravenous amiodarone treatment of 5mg/kg/h for 1 h followed by 0.83mg/kg/h for 23h and subsequently 1.9mg/kg/h for 30h. During treatment, clinical signs were monitored and a surface ECG and an intra-atrial electrogram were recorded. Infusion was discontinued when sinus rhythm or side effects occurred. Four horses successfully cardioverted, of which one showed symptoms of hind limb weakness and weight shifting. Two horses did not cardiovert and showed similar side effects. In all horses, side effects disappeared within 6h after termination of treatment. Cardiac side effects, such as pro-arrhythmia, were not seen in any of the horses. Total bilirubin slightly increased in three horses and normalised within four days. It was concluded that amiodarone has the potential to treat naturally occurring chronic atrial fibrillation in horses, although further research is needed to refine the infusion protocol.     

Animal poisoning in Europe. Part 1: Farm livestock and poultry

The lack of a reference Veterinary Poison Control Centre for the European Union (EU) means that clinicians find it difficult to obtain information on poisoning episodes. This three-part review collates published and unpublished data obtained from Belgium, France, Greece, Italy and Spain over the last decade in order to provide a broader toxicoepidemiological perspective. The first article critically evaluates the national situation in the five European countries and concludes that information for livestock and poultry is limited and fragmentary compared to other animal groups. The analysis has revealed that clinical cases of poisoning are only occasionally studied in depth and that cattle are the species most frequently reported. Several plants and mycotoxins, a few pesticides and metals, together with contaminants of industrial origin, such as dioxins, are responsible for most of the recorded cases.     

Animal poisoning in Europe. Part 3: Wildlife

This review article is the third in a series on animal poisoning in Europe and represents a collation of published and non-published wildlife poisoning data from Belgium, France, Greece, Italy and Spain over the last 10 years. Birds, particularly waterfowl and raptors, were more commonly reported as victims of poisoning than wild mammals. In addition to specific but important toxicological disasters, deliberate primary or secondary poisonings are of concern to all countries. Metals (particularly lead arising from sporting/hunting activities) and pesticides (mainly anticholinesterases and anticoagulants) are frequent causes of poisoning, and often have fatal consequences. A more unified and consistent approach throughout European countries to improve the reporting and the analytical confirmation of wildlife poisoning would help to reduce the number of cases of malicious or negligent animal poisoning.     

Species comparison of oral bioavailability, first-pass metabolism and pharmacokinetics of acetaminophen

Species differences in oral bioavailability, first-pass metabolism and pharmacokinetics of biopharmaceutics classification system (BCS) class I compound acetaminophen were studied. The absolute bioavailability was 42.2%, 39.0%, 44.5%, 75.5% and 91.0% in chickens, turkeys, dogs, pigs and horses, respectively. After hydrolysis of metabolites by β-glucuronidase/sulfatase, apparent bioavailability increased significantly in all species (turkeys: 72.4%, dogs: 100.5%, pigs: 102.2%), except horses (91.6%). Mean metabolic ratios of [acetaminophen glucuronide]/[acetaminophen] between 0 and 1 h were significantly higher after oral dosing in turkeys, dogs and pigs, revealing the role of first-pass metabolism in incomplete bioavailability. Evidence of species differences in acetaminophen metabolism is provided by differences in plasma clearance, which was inversely proportional to bioavailability. In conclusion, differences in BA appeared to originate predominantly from differences in first-pass metabolism, demonstrating that the BCS high permeability classification of acetaminophen is consistent across the mammalian species studied. In turkeys, however, incomplete absorption additionally seemed to contribute to the low BA.