Robert P. Hunter

CONCEPTS AND ISSUES WITH INTERSPECIES SCALING IN ZOOLOGICAL PHARMACOLOGY

Abstract Zoologic medicine practitioners take approved agents (veterinary or human) and extrapolate their use to nonapproved species. The decision on dose, duration, and interval is often made with limited species-specific pharmacokinetic information. Because of the monetary value of these animals or their status as endangered species, this method of “trial and error” for therapeutic dosage selection is inappropriate. In zoologic medicine, various methods have been used in an attempt to extrapolate or predict safe and effective dosage regimens. The simplest and typical method of extrapolating a dosage to a nondomestic species is to use a mg/kg dose established for another domestic species or humans. However, this calculation results in a linear increase in the amount of drug administered as body weight increases. Although common, this method tends to overdose large animals and underdose small animals. The second method is similar, except that it takes the approved dose in a specific species and makes an additional assumption that links the dosage to a physiologic function or anatomic feature. Examples are the use of basal metabolic rate or body-surface area as the basis for dosage extrapolation. Allometric scaling of pharmacokinetic parameters is the final method of dosage extrapolation between species. This is commonly used in the pharmaceutical industry to establish the first dosage in human drug investigations. Adaptation of this method for zoologic medicine may enhance our ability to estimate therapeutic dosages for nondomestic species. This review discusses and compares these three methods for dosage selection and provides examples of extrapolation from the literature.

Simultaneous extraction and quantitation of fentanyl and norfentanyl from primate plasma with LC/MS detection.

The quantitation of both fentanyl and its desalkyl metabolite, norfentanyl, in plasma using LC/MS has not been previously described. The detection and quantitation of fentanyl and norfentanyl was achieved using LC/MS detection. The liquid-liquid extraction used toluene as the organic phase. Chromatography was carried out using a Zirchrom-PBD (50 mm x 2.1 mm, 3 microm) column with a mobile phase of acetonitrile-ammonium acetate (10 mM), citrate (0.1 mM, pH 4.4) (45:55, v/v) with a flow rate of 0.3 ml/min. Mass spectroscopy detection was performed using ESI in the positive mode. The LOQ for fentanyl was 25 pg/ml and norfentanyl was 50 pg/ml. For the concentrations of 75, 250, and 750 pg/ml, respectively, fentanyl had inter-day precisions of 6.6, 7.2, and 6.6% with accuracies of 4.0, 5.1, and 5.1% and intra-day precisions of 1.6, 1.9, and 1.9% with accuracies of 11.6, 9.4, and 8.4%, and norfentanyl had inter-day precisions of 7.4, 0.3, and 0.7% with accuracies of 9.1, 8.8, and 12.3% and intra-day precisions of 5.3, 1.4, and 0.1% with accuracies of 10.9, 8.9, and 12.8%. The recoveries of fentanyl were 85, 92, and 75% and of norfentanyl were 40, 49, and 46% at the 75, 250, and 750 pg/ml concentrations, respectively.

STEADY-STATE PLASMA CONCENTRATIONS OF ITRACONAZOLE AFTER ORAL ADMINISTRATION IN KEMP'S RIDLEY SEA TURTLES, LEPIDOCHELYS KEMPI

Abstract Pharmacokinetic studies of antifungal agents in reptiles are uncommon. Itraconazole, which has been used prophylactically in juvenile sea turtles suffering from hypothermia (cold stunning) on a regular basis, was evaluated for steady-state plasma concentrations. Five Kemps ridley sea turtles (Lepidochelys kempi) receiving itraconazole at several dosages in a rehabilitation program had blood collected within 24 hr to estimate dosing frequency. Subsequently, serial blood samples of Kemps ridley sea turtles that were given itraconazole at several dosages for 30 days to treat cold stunning were collected at various intervals to evaluate itraconazole plasma concentrations. Tissue samples were collected from one Kemps ridley that died during rehabilitation. Plasma concentrations of itraconazole (and of hydroxyitraconazole [OH-ITRA], one of its major bioactive metabolites) were determined using a modified, validated reverse-phase high-performance liquid chromatography technique. Itraconazole concentrations in tissues were determined by bioassay to be far greater than the plasma concentrations measured in any of the turtles. At a 15-mg/kg dosage, the half-life (t1/2) was 75 hr for itraconazole and 55 hr for OH-ITRA. All dosages produced adequate concentrations in some turtles, but consistent therapeutic concentrations were produced only at 15 mg/kg q72hr and 5 mg/kg s.i.d., with the latter producing the highest plasma concentrations.

Single and Multiple-Dose Pharmacokinetics of Meloxicam After Oral Administration to the Rabbit (Oryctolagus cuniculus)

Abstract The nonsteroidal anti-inflammatory drug (NSAID) meloxicam is a very popular anti-inflammatory, analgesic, and antipyretic agent used in veterinary medicine. To determine the pharmacokinetics of this NSAID in rabbits following a single dose and 10-day period of dosing, eight clinically normal, 8-mo-old New Zealand white rabbits (Oryctolagus cuniculus) were administered 0.2 mg/kg meloxicam p.o. daily. Pharmacokinetic analysis of the meloxicam was determined via noncompartmental analysis. After oral administration, mean ± standard deviation values for area under the curve were 1.8 ± 0.50 and 2.1 ± 0.55 µg × h/ml, and maximum plasma concentrations were 0.17 ± 0.06 and 0.24 ± 0.07 µg/ml for Day 1 and Day 10, respectively. The half-life was approximately 8 hr. Administration of meloxicam at a dosage of 0.2 to 0.3 mg/kg p.o. every 24 hr is suggested. Although a higher dose may be required for optimum effects, this would require efficacy and safety studies in this species. Meloxicam administered at 0.2 mg/kg p.o. daily for 10 day was well tolerated by the rabbits.

PRELIMINARY SINGLE-DOSE PHARMACOKINETICS OF MARBOFLOXACIN IN BALL PYTHONS (PYTHON REGIUS)

Abstract Pharmacokinetics of marbofloxacin in two male and four female adult ball pythons (Python regius) was determined after i.v. and p.o. administration of a single dose. Using a crossover design, each snake was given a single 10 mg/kg dose of marbofloxacin i.v. and p.o. Blood samples were collected prior to and 0.5, 1, 1.5, 3, 6, 12, and 24 hr after marbofloxacin administration. Marbofloxacin was quantitated by use of liquid chromatography-mass spectrometry. Following p.o. administration, marbofloxacin had a peak plasma concentration (Cmax) of 9.40 μg/ml and a time to Cmax (Tmax) of 9.0 hr. Based on the plasma pharmacokinetics generated in this study and pending any further studies to evaluate potential toxicity and multi-dose pharmacokinetics, we suggest a dosage for marbofloxacin in ball pythons of 10 mg/kg p.o. at least every 48 hr, depending on the sensitivity of the pathogen and as a basis for further research.

Moxidectin plasma concentrations following topical administration to llamas (Lama glama) and alpacas (Lama pacos)

Producers and veterinarians commonly administer pharmaceuticals labeled for cattle, sheep, or goats to llamas and alpacas, yet little is known about the safety and efficacy of this extra-label usage. There are many species-related factors, such as bioavailability and metabolism, that could lead to variation in the pharmacokinetic parameters between species and possibly decrease the activity of a compound. This experiment investigated the absorption and disposition of topical (pour-on) moxidectin in llamas and alpacas. Seven llamas and seven alpacas were obtained from commercial sources and were not treated with an avermectin/milbemycin agent within 60 days prior to the start of the study. The animals were housed outdoors with water and hay available ad libitum. All animals received moxidectin at a dose of 500g/kg after being clipped along the dorsal midline. Serial blood samples were collected post dose. Samples were analyzed for moxidectin using a validated liquid chromatography/mass spectroscopy assay. Moxidectin administration was well tolerated with no adverse effects noted in either species following topical administration. Median Cmax values were highly variable in the llamas and alpacas with two alpacas having no detectable plasma concentrations of moxidectin. Due to the limited absorption of this compound in both species, appropriate pharmacokinetic parameters could not be determined. In these two species of South American camelids, moxidectin was not well absorbed following topical administration.

Drug Delivery to Captive Asian Elephants - Treating Goliath

Captive Asian elephants have been maintained in captivity by humans for over 4000 years. Despite this association, there is little published literature on the treatment of elephant diseases or methods of drug administration to these animals. Elephants in captivity are generally healthy and require few therapeutic interventions over the course of their lifetime. However, when they become acutely ill, treatment becomes a serious issue. The successful and consistent administration of therapeutics to elephants is formidable in an animal that presents significant limitations in drug delivery options. The single most important factor in administering drugs to an elephant is the animals cooperation in accepting the medication. Working around elephants can be very dangerous and this is magnified when working around sick or injured animals where the elephant is subject to increased stress, pain, and unusual situations associated with treatment. The large body size of the Asian elephant produces a separate set of issues. In this paper, methods of drug administration and their associated limitations will be reviewed. Considerations of medicating such large animals can serve to highlight the problems and principles of treatment that are inherent in these species.

Nitric oxide, inducible nitric oxide synthase and inflammation in veterinary medicine

Abstract Inflammation is a process consisting of a complex of cytological and chemical reactions which occur in and around affected blood vessels and adjacent tissues in response to an injury caused by a physical, chemical or biological insult. Much work has been performed in the past several years investigating inducible nitric oxide synthase (NOS, EC 1.14.13.39) and nitric oxide in inflammation. This has resulted in a rapid increase in knowledge about iNOS and nitric oxide. Nitric oxide formation from inducible NOS is regulated by numerous inflammatory mediators, often with contradictory effects, depending upon the type and duration of the inflammatory insult. Equine medicine appears to have benefited the most from the increased interest in this small, inflammatory mediator. Most of the information on nitric oxide in traditional veterinary species has been produced using models or naturally occurring inflammatory diseases of this species.

Extraction and quantitation of carfentanil and naltrexone in goat plasma with liquid chromatography–mass spectrometry

This method is the first analytical method for the detection and quantitation of carfentanil and naltrexone at clinically relevant concentrations using liquid chromatography-mass spectrometry. Samples were alkalinized with 100 microl of 1 M NaOH and extracted 2x with 2 ml of toluene. The extractions were combined and dried under N(2) at 40 degrees C in a H(2)O bath. Chromatography was performed using a Zirchrom PBD column and a mobile phase of 30:70 acetonitrile/10 mM ammonium acetate and 0.1 mM citrate (pH=4.4) at a flow rate of 0.3 ml/min. The lower limit of quantitation was 8.5 pg/ml for carfentanil and 0.21 ng/ml for naltrexone.

Single- and multiple-dose pharmacokinetics of marbofloxacin after oral administration to rabbits.

OBJECTIVE-To determine the pharmacokinetics of marbofloxacin after oral administration every 24 hours to rabbits during a 10-day period. ANIMALS-8 healthy 9-month-old female New Zealand White rabbits. PROCEDURES-Marbofloxacin (5 mg/kg) was administered orally every 24 hours to 8 rabbits for 10 days. The first day of administration was designated as day 1. Blood samples were obtained at 0, 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours on days 1 and 10 of marbofloxacin administration. Plasma marbofloxacin concentrations were quantitated by use of a validated liquid chromatography-mass spectrometry assay. Pharmacokinetic analysis of marbofloxacin was analyzed via noncompartmental methods. RESULTS-After oral administration, mean +/- SD area under the curve was 10.50 +/- 2.00 microg.h/mL and 10.90 +/- 2.45 microg.h/mL, maximum plasma concentration was 1.73 +/- 0.35 microg/mL and 2.56 +/- 0.71 microg/mL, and harmonic mean terminal half-life was 8.0 hours and 3.9 hours for days 0 and 10, respectively. CONCLUSIONS AND CLINICAL RELEVANCE-Marbofloxacin administered orally every 24 hours for 10 days appeared to be absorbed well and tolerated by rabbits. Administration of marbofloxacin at a dosage of 5 mg/kg, PO, every 24 hours is recommended for rabbits to control infections attributable to susceptible bacteria.