Pharmacokinetics and cardiopulmonary effects of fentanyl in isoflurane-anesthetized rhesus monkeys (Macaca mulatta).

OBJECTIVE: To determine pharmacokinetics and selected cardiopulmonary effects of fentanyl in isoflurane-anesthetized rhesus monkeys. ANIMALS: 6 adult male rhesus monkeys. PROCEDURE: Fentanyl (8 mg/kg of body weight, IV) was administered to 6 monkeys anesthetized with isoflurane. End-tidal isoflurane concentration and esophageal temperature were kept constant, and ventilation was mechanically assisted. Heart rate, rhythm, aortic blood pressure, and blood pH, gas, and fentanyl concentrations were determined before and for 8 hours after administration of fentanyl. Pharmacokinetics of fentanyl were derived by use of noncompartmental methods based on statistical moment theory. RESULTS: Heart rate and mean arterial pressure decreased transiently following fentanyl administration. Maximal decreases were observed 5 to 15 minutes after administration. Arterial pH, Paco2, and Pao2 ranged from 7.46 +/- 0.04 to 751 +/- 0.05 units, 29.2 +/- 3 to 34.6 +/- 4.4 mm Hg, and 412.6 +/- 105.3 to 482.9 +/- 71.2 mm Hg, respectively. The clearance, volume of distribution area, volume of distribution steady state, mean residence time, area under the curve, elimination rate constant, and half-life were 32.5 +/- 2.48 ml/kg/min, 9.04 +/- 1.91 L/kg, 70 +/- 1.2 L/kg, 218.5 +/- 35.5 min, 0.247 +/- 0.019 mg/ml/min, 0.004 + 0.001/min, and 192.0 +/- 33.5 min, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Transient but potentially clinically important decreases in heart rate and mean arterial pressure were observed following fentanyl administration. Distribution and clearance data were similar to those reported for dogs and humans.

Antimicrobial selection, administration and dosage.

Various types of information contribute to the selection of an antimicrobial agent. Initial requirements are diagnosis of the site and nature of the infection, assessment of the severity of the infectious process and medical condition of the diseased animal; these are embodied in clinical experience. Additional considerations include identification of the causative pathogenic microorganism, knowledge of its susceptibility to antimicrobial agents (microbiological considerations) and of the pharmacokinetic properties of the drug of choice and alternative drugs, and their potential toxicity (pharmacological considerations) in the animal species. Select an antimicrobial drug and dosage form appropriate for use in the particular animal species. Usual dosage regimens may be applied, except in the presence of renal or hepatic impairment, when either modified dosage or a drug belonging to another class should be used. The duration of therapy is determined by monitoring the response both by clinical assessment and bacterial culture. A favourable clinical response is the ultimate criterion of successful therapy.

Comparison of the pharmacokinetics and local tolerance of three injectable oxytetracycline formulations in pigs.

The pharmacokinetic properties and local tolerance of three oxytetracycline formulations, one conventional (Engemycine, 10%) and two long-acting (Oxyter LA, 20% and Terramycin LA, 20%) were compared in clinically healthy cross-bred pigs following intramuscular injection of single doses (20 mg/kg body weight) in the neck region. Non-compartmental methods were used to calculate the pharmacokinetic parameters. Assessment of local tolerance was based on serum creatine phosphokinase (CPK) concentration and a combination of echographical, macroscopic and histological examinations of the intramuscular injection site. Statistically significant differences (one-way analysis of variance, F-test) were obtained between the three formulations in peak plasma concentration, peak time and mean residence time. Area under the curve did not differ significantly between the formulations. Using the Students t-test for paired data, the two long-acting formulations differed significantly in peak plasma concentration and peak time. Both of the long-acting formulations differed significantly from the conventional formulation in the peak time and mean residence time. All three formulations produced an increase in serum CPK concentrations. The increase in CPK concentration was present from 6 to 24 h post treatment for Terramycin LA, from 6 to 72 h for Oxyter LA and from 6 to 96 h for Engemycine (the conventional formulation). Echographical examination of the injection site showed lesions of an inflammatory type up to 96 h after IM injection of the drug products, whereas from 7 days the lesions represented primarily scar formation. Histological examination of tissue from the injection site did not correlate with echographical scores. The results obtained in this study show that the long-acting formulations provide significantly longer mean residence times of oxytetracycline than the conventional formulation, and that local tolerance at the IM injection site was similar for all three formulations under the experimental conditions used in this study. It can be concluded that the long-acting formulations provide the advantage of a longer dosage interval when administered to pigs by intramuscular injection in the neck region at a dose of 20 mg/kg body weight.

Effect of ingesta and of tablets of different strengths on the systemic availability of digoxin in normal dogs.

The plasma concentrations of digoxin were measured in eight normal dogs given digoxin on four occasions, using three different feeding regimens and tablets of two strengths. Although ingesta tended to slow the absorption of digoxin, the systemic availability of the drug, based on measurements of Cmax, tmax and AUC did not differ when digoxin tablets were given with canned food, with dry food, or without food. However, some of the pharmacokinetic characteristics and smaller individual variations with the dry food regimen would be considered advantageous for maintenance therapy. Tablets containing 62.5 micrograms or 250 micrograms of digoxin had a similar relative bioavailability. The peak plasma digoxin concentrations were higher in female dogs, and the trends in other data also suggested that the systemic availability of digoxin was better in female dogs.

Comparative pharmacokinetics of amoxicillin/clavulanic acid combination after intravenous administration to sheep and goats.

The pharmacokinetic behaviour of an amoxicillin/clavulanic acid combination was studied after intravenous administration of single doses (20 mg/kg per kg body weight) to five sheep and six goats. The objective was to determine whether there are differences between sheep and goats in the disposition of amoxicillin and clavulanic acid. The plasma concentration-time data were analysed by compartmental pharmacokinetic and non-compartmental methods. The disposition curves for both drugs were best described by a biexponential equation (two-compartment open model) in sheep and goats. The elimination half-lives of amoxicillin were 1.43 +/- 0.16 h in sheep and 1.13 +/- 0.19 h in goats, and of clavulanic acid were 1.16 +/- 0.01 h and 0.85 +/- 0.09 h in sheep and goats respectively. The apparent volumes of distribution of amoxicillin and clavulanic acid were similar in the two species. Body clearances of amoxicillin were 0.09 +/- 0.01 L/h kg in sheep and 0.11 +/- 0.01 L/h kg in goats, and of clavulanic acid were 0.07 +/- 0.01 L/h kg and 0.12 +/- 0.01 L/h kg in sheep and goats respectively. The half-lives and body clearances of amoxicillin and clavulanic acid differed significantly between sheep and goats. It was concluded that the disposition of amoxicillin and clavulanic acid administered intravenously as an amoxicillin/clavulanic acid combination to sheep and goats differed between the two ruminant species. Even though the differences in disposition kinetics of both drugs were statistically significant, the same intravenous dosing rate of this antimicrobial combination can generally be used in sheep and goats.

Morphine-isoflurane interaction in dogs, swine and rhesus monkeys.

In monkeys, dogs and swine (six each) we tested the reduction of the isoflurane MAC (minimal alveolar concentration) produced by 2 mg.kg-1 morphine intravenously (i.v.) and the concurrent effect on PCO2 with spontaneous ventilation. MAC fell to a minimum of 55% of control at 53 min in monkeys, 50% at 38 min in dogs and 13% at 33 min in swine. PaCO2 rose at constant MAC with morphine to 55-60 mmHg, but did not fall over the next several hours despite the decline of plasma morphine concentration, and the resulting needed rise in isoflurane concentration to keep the anaesthesia depth at 1 MAC. After isoflurane concentration had returned to pre-morphine control levels, naloxone immediately reduced PaCO2 to or below control level. Morphine pharmacokinetics in the three species studied conformed to a two-compartment model.

Application of interspecies scaling to the bispyridinium oxime HI-6.

Disposition kinetic variables of HI-6, a bispyridinium oxime, have been determined in mice, rats, rabbits, Rhesus monkeys, Beagles, sheep, and human beings. The drug has a short half-life, small apparent volume of distribution and high body clearance in these species, and is eliminated mainly by renal excretion. Using regression analysis and double logarithmic plots of the pharmacokinetic variables vs body weight of the various species, it was observed that body (systemic) clearance is the pharmacokinetic variable to use for interspecies comparison of elimination of the drug. The allometric exponent denoting the proportionality of body clearance of HI-6 to body weight of the 7 species studied was 0.76, which may be related to the renal excretion process for the drug. The apparent volume of distribution was similar (260 to 304 ml/kg of body weight) in the various species. The results indicate that volume of distribution, body clearance, and with less confidence, half-life might be used for interspecies scaling and for predicting these variables in other mammalian species. On the basis of the pharmacokinetic variables in selected species (rats and mice excluded), i.v. administration of HI-6 at a dosing rate of 20 to 25 mg/kg at 4-hour intervals should provide an average steady-state plasma concentration of 16 to 20 micrograms/ml in domestic animals. The short half-life of HI-6 precludes increasing the dosage interval.

Drug therapy in the neonatal foal.

The neonatal period in foals refers to the first 7 days of postnatal life. The effects of drugs (pharmacologic agents) may be different in neonatal foals, particularly during the first 3 days of postnatal life, from those in older foals and adult horses. The changed drug effects decrease as the physiologic processes that affect absorption, distribution, and elimination (metabolism and excretion) of drugs mature. Dosage regimens should take into account the altered pharmacokinetic profiles of drugs, and because of wide individual variation, the response to therapy should be closely monitored for signs of toxicity. In conjunction with the prudent use of drugs, good nursing care and the provision of supportive therapy are critical in the management of neonatal foal diseases. Over-crowding imposes stress upon young foals and predisposes them to an increased incidence of bacterial and parasitic infections. The collection of specimens for precise microbiologic diagnosis and correction of deficits in serum immunoglobulins should precede antimicrobial therapy. Although E. coli is by far the most common cause of bacterial infections in neonatal foals, other bacterial pathogens of unpredictable susceptibility often cause infection. The selection of an antimicrobial drug for specific therapy should be based on both the microbiologic (quantitative susceptibility) and pharmacologic (pharmacokinetic) properties of the drug. The use of an antimicrobial drug or combination of drugs that will produce a bactericidal effect is highly desirable. Whenever possible, a parenteral preparation that can be administered intravenously should be chosen. The bioavailability and selectivity of action of pharmacologic agents are influenced by the dosage form and route of administration. Diazepam is the sedative drug of choice for neonatal foals. Cimetidine, an H2-receptor antagonist, may be indicated in foals diagnosed to have gastric ulcers; hepatic microsomal oxidative metabolism of drugs administered concurrently with cimetidine is decreased. Nonsteroidal anti-inflammatory drugs (flunixin, phenylbutazone) have a higher incidence of toxicity in foals and, when indicated, should be used at lower dosage than in adult horses. Even though it is highly important to maintain hydration status and electrolyte balance, intravenous infusion should always be performed slowly. Immature renal function decreases the ability of the neonatal animal to excrete excess fluid. The use of drugs in neonatal foals requires greater precision in dosage, more attention to the route and rate of administration, and close monitoring of pharmacologic effects.

Pharmacokinetics of tobramycin in the camel.

The pharmacokinetics of tobramycin were determined in six healthy camels (Camelus dromedarius) following the intravenous (i.v.) and intramuscular (i.m.) administration of single doses of tobramycin sulphate (40 mg/ml). The half-life to tobramycin was 189 +/- 21 min and the mean residence time was 254 +/- 26 min. The apparent volume of distribution (area method) was 245 +/- 21 ml/kg, while volume of the central compartment of the two-compartment pharmacokinetic model was 110 +/- 12 ml/kg. The clearance (systemic) of tobramycin was 0.90 +/- 0.10 ml/min/kg. Values of the pharmacokinetic parameters suggest that glomerular filtration rate is lower in camels than in other ruminant species, horses, dogs and cats. Following i.m. administration of the dose (1.0 mg/kg), the drug was rapidly absorbed with peak serum concentration of 3.32 +/- 0.59 micrograms/ml at 20-30 min; the absorption half-life was 3.9 +/- 0.9 min. The systemic availability of tobramycin was 90.7 +/- 14.4%. The apparent half-life was 201 +/- 40 min, which was not significantly longer than the half-life following i.v. administration of the drug. Based on the pharmacokinetic values obtained in this study, a dosing rate of 2.5 mg/kg administered by i.m. injection at 12-h intervals can be recommended. This dosage regimen should achieve an average steady state serum concentration of 4 micrograms/ml with peak serum concentration approaching, but not exceeding, 10 micrograms/ml.

Influence of inhaled anesthetics on the pharmacokinetics and pharmacodynamics of morphine.

We determined the magnitude and duration of the effect of morphine (1.0 mg/kg intravenous bolus) on isoflurane and halothane minimum alveolar concentration (MAC) in six dogs anesthetized on two occasions in cross-over fashion. Plasma morphine concentration-time profiles and changes in PaCO2 were determined after morphine injection. After morphine injection, the end-tidal anesthetic dose was manipulated over the course of a 4-h observation period to account for the decline in plasma morphine concentration and to maintain an anesthetic level equivalent to 1.0 MAC isoflurane or halothane alone. Morphine decreased the MAC of halothane and isoflurane. The magnitude of MAC decrease was related to time after morphine injection and was similar for a given time with both halothane and isoflurane. For example, at 28.8 +/- 3.6 (mean +/- SE) and 34.8 +/- 6.3 min after morphine injection, the MAC for halothane and isoflurane were reduced by 35.7% +/- 4.5% and 39.3% +/- 3.4%, respectively. By 4 h after morphine injection, the MAC reduction for both anesthetics was less than 10% in most of the animals. Except for systemic clearance of morphine during halothane and isoflurane (40.1 +/- 6.1 and 53.7 +/- 5.6 mL.min-1.kg-1, respectively), there were no differences in disposition kinetics of free morphine associated with the two inhaled anesthetics. Morphine increased PaCO2 to a similar degree with both halothane (from 42.2 +/- 2.1 mm Hg to 55.6 +/- 2.3 mm Hg) and isoflurane (46.2 +/- 2.4 mm Hg to 55.3 +/- 2.1 mm Hg). Respiratory depression was abolished by noxious stimulation (tail clamp) and naloxone in all animals with both anesthetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioavailability and disposition kinetics of HI-6 in Beagle dogs.

The absorption and disposition kinetics of HI-6 were determined in Beagle dogs given single doses (25 mg kg-1) of the drug by the intravenous, intramuscular, and oral routes. Concentrations of the oxime in plasma and urine were measured by HPLC. A two-compartment open model was used to describe the disposition curve following intravenous drug administration while a one-compartment open model with first-order absorption adequately described the data following intramuscular or oral administration of the dose. Extravascular distribution of HI-6 was limited (Vss 203 ml kg-1) and the drug was eliminated rapidly after intravenous administration (t1/2 46.5 min, MAT 55.4 min). Systemic clearance was 3.68 ml min-1 x kg. A major fraction of the dose (63.7 per cent) was excreted in urine over a 24-h collection period. Following intramuscular drug administration, the absorption half-life (t1/2(a), 5.3 min), MAT (17.1 min), Cmax (70.37 micrograms ml-1) and tmax (15.9 min) indicate that the drug was rapidly absorbed. Systemic availability was 83.43 per cent after oral drug administration, absorption was preceded by a lag time (23.2 min). The t1/2(a) (41.5 min), MAT (81.6 min), Cmax (4.30 micrograms ml-1) and Tmax (90.6 min) indicate somewhat delayed absorption. Systemic availability (11.38 per cent) and the fraction of dose excreted unchanged in the urine (9.3 per cent) show that the drug was poorly absorbed. The apparent half-life (58.0 min) and MRT (137.6 min) following oral administration were significantly longer (p < 0.05) than following intravenous or intramuscular administration suggesting that the rate of absorption from the gastrointestinal tract decreases the elimination rate of the drug. In conclusion, HI-6 has limited distribution within the body, is rapidly eliminated mainly by renal excretion unchanged in the urine, and the bioavailability (i.e. rate and extent of absorption) of the drug varies with the route of administration.

Plasma profiles of albendazole metabolites after administration of netobimin and albendazole in sheep: effects of parasitism and age.

Netobimin and albendazole were administered to 3-month-old lambs with moderate infections of Nematodirus battus and to comparable parasite-naive lambs. Albendazole sulphoxide and albendazole sulphone concentrations were determined in the plasma of all lambs at frequent intervals after treatment. Both anthelmintic preparations were 100% effective in reducing nematode faecal egg output in the lambs. There were no significant differences in the concentrations of the sulphoxide or sulphone metabolites in parasitized compared with non-parasitized lambs given the same parent anthelmintic. The parasite-naive lambs were subsequently weaned and maintained indoors in conditions designed to preclude nematode parasite infection until they were 9 months old. Netobimin and albendazole were administered again and the plasma profiles of the albendazole sulphoxide and albendazole sulphone metabolites determined. There were no significant differences in the plasma distribution of these metabolites with age of the lambs. The area under the plasma concentration time curve, mean resident time and apparent half-life of the albendazole sulphoxide metabolite was determined following administration of each parent drug and the clearance of the metabolite/systemic availability of parent drug was determined as a marker of the amount of drug available for metabolism. There were no significant differences in pharmacokinetic variables between parasitized and non-parasitized animals nor with the age of the animals.

Bioavailability and bioequivalence of veterinary drug dosage forms, with particular reference to horses: an overview.

The route of administration and formulation of the dosage form affect the bioavailability (rate and extent of absorption) of a drug and may thereby influence the intensity and duration of the pharmacological effect. Location of injection site may affect the plasma concentration profile of drugs administered as aqueous suspensions or sustained release parenteral preparations (procaine penicillin G). When absorption influences the rate of elimination ('flip-flop' phenomenon), the apparent half-life of the drug will be increased (cefazolin sodium, i.m.; meclofenamic acid, p.o.). Absorption generally approximates a first-order process and either the absorption half-life or the mean absorption time (statistical moment term) will provide an estimate of the rate of absorption. The method of corresponding areas is the usual technique employed in estimating the extent of absorption (systemic availability). Inherent in this technique is the assumption that clearance of the drug remains unchanged. In horses, the time of feeding relative to oral dosing has been shown to affect systemic availability (rifampin, trimethoprim) and pattern of absorption (phenylbutazone). Oral paste formulations (trimethoprim-sulphadiazine, ivermectin) are convenient to administer, allow precision in dosage compared with powders or granules added to feed, and could provide sustained release. Assessment of bioequivalence is based on relative bioavailability, using a reference dosage form, together with a measure of the uncertainty (variance) of the estimate. Bioequivalence relies on the concept that preparations of a drug which provide essentially equivalent plasma concentration profiles should produce the same therapeutic effect.

Clinical pharmacokinetics in veterinary medicine.

Veterinary and human pharmacology differ principally in the range of species in which drugs are used and studied. In animals, as in humans, an understanding of the dose-effect relationship can be obtained by linking pharmacokinetic behaviour with pharmacodynamic information. Studies of different classes of drugs support the assumption that the range of therapeutic plasma concentrations in animals is generally the same as in humans. The requirement for species differences in dosage or administration rate (dose/dosage interval) may be attributed to variations in pharmacokinetic behaviour or pharmacodynamic activity, or both. When administering a drug orally, the bioavailability from a dosage form can vary widely. This is particularly the case between ruminant animals (cattle, sheep and goats), horses and carnivorous species (dogs and cats). Species variations in bioavailability can be avoided by parenteral administration. Formulation of parenteral preparations and location of intramuscular injection site can, at least in horses and cattle, influence bioavailability. Comparative pharmacokinetic studies help to explain differences in absorption and disposition processes that may underlie species variations in response to fixed dosages of a drug. Certain marker substances are useful in quantifying the activity of metabolic pathways or efficiency of excretion processes. Prediction of preslaughter withdrawal times in food-producing animals represents an application of pharmacokinetics in the field of drug residues. The drug residue profile can be obtained by combining fixed dose pharmacokinetic studies with measurement of drug concentrations in selected tissues and organs of the body. This approach offers an economical advantage in that fewer animals are required for residue studies. In domestic animals, as in humans, the disposition of most drugs can be interpreted in terms of a 2- (generally) or 3-compartment open model. Species variations in pharmacokinetic behaviour of a drug are usually attributed to differences in the rate of elimination rather than distribution and metabolism of the drug, although the principal metabolic pathway may differ. With certain notable exceptions, the herbivorous species (horses and ruminant animals) metabolise lipid-soluble drugs more rapidly than carnivorous species (dogs and cats). Humans metabolise drugs slowly in comparison with animals. Half-life values reflect this; insufficient data are available to base interspecies comparison on mean residence time. Intrinsic hepatic clearance of phenazone (antipyrine) [microsomal oxidation] in humans is approximately one-seventh of that in domestic animals.(ABSTRACT TRUNCATED AT 400 WORDS)