Journal of Veterinary Pharmacology and Therapeutics

Terminal plasma half‐life is the time required to divide the plasma concentration by two after reaching pseudo‐equilibrium, and not the time required to eliminate half the administered dose. When the process of absorption is not a limiting factor, half‐life is a hybrid parameter controlled by plasma clearance and extent of distribution. In contrast, when the process of absorption is a limiting factor, the terminal half‐life reflects rate and extent of absorption and not the elimination process (flip‐flop pharmacokinetics). The terminal half‐life is especially relevant to multiple dosing regimens, because it controls the degree of drug accumulation, concentration fluctuations and the time taken to reach equilibrium.

The clinical effects and pharmacokinetics of medetomidine (MED) and its enanti‐omers, dexmedetomidine (DEX) and levomedetomidine (LEVO) were compared in a group of six beagle dogs. The dogs received intravenously (i.v.) a bolus of MED (40 μg/kg), DEX (20 and 10 μg/kg), LEVO (20 and 10 μg/kg), and saline placebo in a blinded, randomized block study in six separate sessions. Sedation and analgesia were scored subjectively, and the dogs were monitored for heart rate, ECG lead II, direct blood pressure, respiratory rate, arterial blood gases, and rectal body temperature. Blood samples for drug analysis were taken. Peak sedative and analgesic effects were observed at mean (± SD) plasma levels of 18.5 ± 4.7 ng/mL for MED40, 14.0 ± 4.5 ng/mL for DEX20, and 5.5 ± 1.3 ng/mL for DEX10. The overall level of sedation and cardiorespiratory effects did not differ between MED40, DEX20 and DEX10 during the first hour, apparently due to a ceiling effect. However, the analgesic effect of DEX20 lasted longer than the effect of the corresponding dose of racemic medetomidine, suggesting greater potency for dexmedetomidine in dogs. Levomedetomidine had no effect on cardio‐vascular parameters and caused no apparent sedation or analgesia. The pharmacokinetics of dexmedetomidine and racemic medetomidine were similar, but clearance of levomedetomidine was more rapid (4.07 ± 0.69 L/h/kg for LEVO20 and 3.52 ± 1.03 for LEVO10) than of the other drugs (1.26 ± 0.44 L/h/kg for MED40, 1.24 ± 0.48 for DEX20, and 0.97 ± 0.33 for DEX10).

Plasma (total, systemic…) clearance is determined by all the individual metabolizing/eliminating organ clearances and involves mainly liver and kidney clearances. Plasma clearance (a volume per time, i.e. a flow) expresses the overall ability of the body to eliminate a drug by scaling the drug elimination rate (amount per time) by the corresponding plasma concentration level. The interpretation of plasma clearance and inter‐species comparisons are made easier by computing the overall body extraction ratio (from 0 to 1), which is the ratio of the body clearance divided by cardiac output. Plasma clearance is the most important pharmacokinetic parameter because it is the only one which controls the overall drug exposure (for a given bioavailability) and it is the parameter which allows computation of the dosage required to maintain an average steady‐state plasma concentration.

The pharmacokinetic disposition of xylazine hydrochloride is described after both intravenous and intramuscular injection of a single dose, in four domestic species: horse, cattle, sheep and dog, by an original high performance liquid chromatographic technique. Remarkably small interspecific differences are reported. After intravenous administration, systemic half‐life (t_{1/2 β}) ranged between 22 min (sheep) and 50 min (horse) while the distribution phase is transient with half‐life (t_{1/2 α}) ranging from 1.2 min (cattle) to 5.9 min (horse). The peak level of drug concentration in the plasma is reached after 12–14 min in all the species studied following intramuscular administration. Xylazine bioavailability, as measured by the ratios of the areas under the intravenous and intramuscular plasma concentration versus time curves, ranged from 52% to 90% in dog, 17% to 73% in sheep and 40% to 48% in horse. The low dosage in cattle did not permit calculation. Kinetic data are correlated with clinical data and the origins of interspecific differences are discussed.

Varma, K.J., Adams, P.E., Powers, T.E., Powers, J.D. & Lamendola, J.F. Pharmacokinetics of florfenicol in veal calves. J. vet. Pharmacol. Therap. 9, 412–425.

The pharmacokinetic disposition of florfenicol was described in veal calves after administration of a single 22‐mg/kg dose intravenously, orally after a 12‐h fast and orally 5 min post feeding. Both serum concentrations and urinary excretion were studied. After intravenous administration the median elimination half‐life was 171.9 min while the half‐life of the distribution phase was 5.9 min. The median body clearance (Cl) and apparent volume of distribution (V_z) were 2.85 ml/kg/min and 0.78 1/kg, respectively. Following oral administration the median bio‐availability (f) was 0.88 for calves dosed after a 12‐h fast and 0.65 for calves dosed 5 min post feeding. Calves given the oral doses had a complex absorption pattern with delayed absorption. Slightly more than 50% of the administered dose both orally and intravenously was recovered as unchanged florfenicol in the urine by 30 h.

Eugenol, the principle chemical constituent of clove oil, has recently been evaluated for its anesthetic and analgesic properties in fish and amphibians. The objective of this study was to determine the pharmacokinetic (PK) and anesthetic activity of eugenol in rats. Male Sprague–Dawley rats received single i.v. doses of eugenol (0, 5, 10, 20, 40 and 60 mg/kg) and anesthetic level was evaluated with the withdrawal reflex. For the 20 mg/kg dose level, blood and urinary samples were collected over 1 h for the PK assessment. Plasma and blood concentrations of eugenol, as well as metabolite identification in urine, were determined using a novel dansyl chloride derivatization method with liquid chromatography mass spectrometry (LC/MS/MS). PK parameters were calculated using noncompartmental methods. Eugenol‐induced loss of consciousness in a dose‐dependent manner, with mean (±SEM) recovery in reflex time of 167 ± 42 sec observed at the highest dose level. Mean systemic clearance (Cl) in plasma and blood were 157 and 204 mL/min/kg, respectively. Glucuronide and sulfate conjugates were identified in urine. Overall, eugenol produced a reversible, dose‐dependent anesthesia in male Sprague–Dawley rats.

The pharmacokinetics of intravenously and orally administered enrofloxacin was determined in fingerling rainbow trout (Oncorhymhur mykiss). Doses of 5 or 10 mg enrofloxacin /kg body weight were administered intravenously to 26 fish for each dose and blood was sampled over a 60‐h period at 15°C. Two groups of fish were treated orally with 5, 10, or 50 mg/kg (80 fish/dose at each temperature) and held at 15°C or 10°C during the 60‐h sampling period. Following intravenous administration, the serum concentration—time data of enrofloxacin in rainbow trout were best described by a two‐compartment open model for both doses of 5 and 10 mg enrofloxacin/kg. The hybrid rate constants a and β did not differ between doses. The distributional phase was rapid with a half‐life of 6–7 min for both doses. Overall half‐lives of elimination were 24.4 h (95% CI = 20.2–30.8) and 30.4 h (24.241.0), respectively, for the 5– and 10‐mg/ kg doses. A large V_d(area) was observed following dosing of either 5 or 10 mg enrofloxacin/kg,: 3.22 and 2.56 l/kg, respectively. Whole body clearance for 5 mg/kg was 92 ml/h.kg and 58 ml/h‐kg at the 10‐mg/kg dose. Following oral administration, the serum concentration—time data for enrofloxacin were best described as a one‐compartment open model with first‐order absorption and elimination. Apparent K_a over all doses at 10°C averaged 62% less than apparent K_a, at 15°C. Estimates of the apparent t_(1/2)e over both temperatures ranged from 29.5 h (18.4–73.4) to 56.3 h (38.3–106.6). Bioavailability averaged 42% over all doses at 15°C and was decreased to an average of 25% at 10°C. Peak serum concentrations appeared between 6 and 8 h following dosing. A dose of 5 mg/kg/ day was estimated to provide average steady‐state serum concentrations at 10°C that are approximately 4.5 times the highest reported MIC values for Streptococcus spp., the fish pathogen least sensitive to enrofloxacin. Owing to the long apparent half‐life of elimination of enrofloxacin in fingerling trout, it would take approximately 5 to 9 days to achieve these predicted steady‐state serum concentrations; this estimate is important when considering the duration of therapy in clinical trials.

This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food‐producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food‐producing animals. The advantages and disadvantages of PBPK modeling compared to other pharmacokinetic modeling approaches (i.e., classical compartmental/noncompartmental modeling, nonlinear mixed‐effects modeling, and interspecies allometric scaling) are further presented. The review finally discusses contemporary challenges and our perspectives on model documentation, evaluation criteria, quality improvement, and offers solutions to increase model acceptance and applications in veterinary pharmacology and toxicology.

Pharmacodynamics (PDs) is the science of drug action on the body or on microorganisms and other parasites within or on the body. It may be studied at many organizational levels – sub‐molecular, molecular, cellular, tissue/organ and whole body – using in vivo, ex vivo and in vitro methods and utilizing a wide range of techniques. A few drugs owe their PD properties to some physico‐chemical property or action and, in such cases, detailed molecular drug structure plays little or no role in the response elicited. For the great majority of drugs, however, action on the body is crucially dependent on chemical structure, so that a very small change, e.g. substitution of a proton by a methyl group, can markedly alter the potency of the drug, even to the point of loss of activity. In the late 19th century and first half of the 20th century recognition of these facts by Langley, Ehrlich, Dale, Clarke and others provided the foundation for the receptor site hypothesis of drug action. According to these early ideas the drug, in order to elicit its effect, had to first combine with a specific ‘target molecule’ on either the cell surface or an intracellular organelle. It was soon realized that the ‘right’ chemical structure was required for drug–target site interaction (and the subsequent pharmacological response). In addition, from this requirement, for specificity of chemical structure requirement, developed not only the modern science of pharmacology but also that of toxicology. In relation to drug actions on microbes and parasites, for example, the early work of Ehrlich led to the introduction of molecules selectively toxic for them and relatively safe for the animal host.

In the whole animal drugs may act on many target molecules in many tissues. These actions may lead to primary responses which, in turn, may induce secondary responses, that may either enhance or diminish the primary response. Therefore, it is common to investigate drug pharmacodynamics (PDs) in the first instance at molecular, cellular and tissue levels in vitro, so that the primary effects can be better understood without interference from the complexities involved in whole animal studies.

When a drug, hormone or neurotransmitter combines with a target molecule, it is described as a ligand. Ligands are classified into two groups, agonists (which initiate a chain of reactions leading, usually via the release or formation of secondary messengers, to the response) and antagonists (which fail to initiate the transduction pathways but nevertheless compete with agonists for occupancy of receptor sites and thereby inhibit their actions). The parameters which characterize drug receptor interaction are affinity, efficacy, potency and sensitivity, each of which can be elucidated quantitatively for a particular drug acting on a particular receptor in a particular tissue. The most fundamental objective of PDs is to use the derived numerical values for these parameters to classify and sub‐classify receptors and to compare and classify drugs on the basis of their affinity, efficacy, potency and sensitivity.

This review introduces and summarizes the principles of PDs and illustrates them with examples drawn from both basic and veterinary pharmacology. Drugs acting on adrenoceptors and cardiovascular, non‐steroidal anti‐inflammatory and antimicrobial drugs are considered briefly to provide a foundation for subsequent reviews in this issue which deal with pharmacokinetic (PK)–PD modelling and integration of these drug classes. Drug action on receptors has many features in common with enzyme kinetics and gas adsorption onto surfaces, as defined by Michaelis–Menten and Langmuir absorption equations, respectively. These and other derived equations are outlined in this review. There is, however, no single theory which adequately explains all aspects of drug–receptor interaction. The early ‘occupation’ and ‘rate’ theories each explain some, but not all, experimental observations. From these basic theories the operational model and the two‐state theory have been developed. For a discussion of more advanced theories see Kenakin (1997).