2006 merck/merial - School of Veterinary Medicine - Louisiana State ...

Evaluation of the pharmacokinetics of opioid drugs in GreyhoundsStacy Borum*, Butch KuKanich, PhD, DVM, DACVCPAnalytical Pharmacology Lab, Kansas State University College of Veterinary Medicine, Manhattan, KSIt has been theorized that Greyhounds differ from other breeds when it comes to the pharmacokinetics of somedrugs. The purpose of this study was to determine the effects and disposition of opioids in Greyhounds and whether theyneed to be dosed differently in clinical situations. The hypothesis for this study is that Greyhounds do not differ in theirdisposition of opioids, and therefore may be given the same dose as other dogs. In this study six Greyhounds, 3 males and 3females, were used. Each dog was given 0.5 mg/kg IV morphine sulfate and blood was drawn through a central line jugularcatheter at specific intervals. In a different phase the dogs were given 0.5 mg/kg IV methadone and blood was drawn in asimilar manner at specific time intervals. Morphine is metabolized through glucuronidation, while methadone is oxidativelymetabolized. These are the two primary methods of metabolism of opioids. The methodology for analysis of each sample inthe morphine study included HPLC and mass spectrometry. Methadone was analyzed with a florescence polarizationimmunoassay (FPIA). Computer analysis assessed the concentration of drug over time. The terminal half-life, volume ofdistribution, and clearance of the morphine and methadone were determined for each dog. Both drugs were well-tolerated bythe Greyhounds. The data suggest that these pharmacokinetics are similar to previously researched values in other studiesthat have been conducted on different breeds. In conclusion, Greyhounds do not need to be dosed differently in regards toopioids in clinical situations.Unraveling pharmacogenomics in companion animals: an In vitro approachSarah Burton, Chris Carmichael, Dr. Dawn BootheAuburn University College of Veterinary MedicinePharmacogenomic research regarding the role of species differences in drug metabolism has been limited. The useof an in vitro model for studying drug metabolizing enzymes (DME) that can predict in vivo metabolism could advanceveterinary drug therapy. Such a model for animals would allow proactive comparative studies to detect differences in DMEthat might lead to therapeutic failure or adverse drug events, including drug interactions. Tissue slices have been establishedas an in vitro model for the study of DME in a variety of human and rodent models. Slices maintain cell to cell interactionsand thus more closely resemble in vivo models compared with cell cultures. This study was conducted to: 1. establishoptimal conditions for incubation of dog and cat hepatic slices, 2. to determine the length of viability of the slices duringincubation, and 3. to compare the metabolism of diazepam (DZP) between canine and feline. DZP was chosen as a modeldrug because it is metabolized to active and/or potentially toxic metabolites. The cat is known to be deficient in DME andpredisposed to adverse reactions to DZP. Our hypothesis is that DZP metabolism in feline liver slices will differquantitatively and qualitatively compared to canine and these differences play a role in DZP toxicity. Hepatic slices fromnormal dogs and cats were incubated for up to 48 hours in varying concentrations of DZP. Slices were homogenized then themedia and supernatant were analyzed for viability and DZP metabolism, indicated by disappearance of DZP and appearanceof metabolites (oxazepam, temazepam and nordiazepam). The amount of adenosine triphosphate and potassium weremeasured to determine viability, higher concentrations indicated healthier slices. Results indicate viability for at least 24hours, and nordiazepam as the major metabolite in dogs verses temazepam in cats. Studies are in progress to confirm theseresults and show a correlation to DZP induced hepatotoxicity.Age-Related Differences in Detoxication and Acute Toxicity Levels of Organophosphate Compounds in RatsWhitney Anne Butler*, Edward C. Meek and Janice E. ChambersCenter for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University,Mississippi State, MSOrganophosphorus insecticides are a commonly used group of compounds that have been implicated inneurodevelopmental disorders in infants and children. The main mechanism of action of these compounds, on both target andnontarget species, is inhibition of acetylcholinesterase (AChE). The organophosphate insecticides (OPs) display a wide rangeof acute toxicity levels, and show greater acute toxicity in juveniles than adults. Previous studies using the active metabolites(oxons) of these OPs have shown that the greater ability of adults to detoxify OPs is an important factor in the greater toleranceof these compounds by adults. This study investigates the age related patterns of toxicity and detoxication of the parent OPinsecticides. One diethyl OP, chlorpyrifos (CPS), and one dimethyl OP, methyl parathion (MPS) were selected for testing invivo. Brain and serum AChE and liver and serum carboxylesterase (CbxE) were investigated at ages 70 (adult), 12 (juvenile),and 1 (neonate) days of age. Rats were exposed IP to each of the OPs to determine the dosages required to inhibit brain AChEat 3 levels (80-90%, 40-50%, and 10-20%) for MPS and 2 levels (40-50% and 10-20%) for CPS. Dosages selected for MPSwere approximately 2 fold higher in adults than in juveniles and neonates, and for CPS were approximately 6 fold higher inadults than in juveniles and neonates. Rats were sacrificed at 3 hours post injection and both enzymes were assayedspectrophotometrically. The differences in toxicity among the 3 ages was much greater for CPS than MPS these results support133