Peculiarities of pharmacokinetics in young animals

In young animals, especially in newborns, absorption, distribution, metabolism and elimination of drugs differ markedly from adults. Respective differences and the cause of these differences are described, including some examples of drug pharmacokinetics in young and adult animals of different species. However, the estimation of pharmacokinetic differences and their pharmacological consequences in young animals is not generally possible, because published data on characteristics of pharmacokinetics in young animals are available only for relatively few drugs. Furthermore, such estimation is complicated by an interaction of different pharmacokinetic processes. Thus, a generally accepted adaptation of dosage schedules for drugs in young animals cannot be offered as yet. In any event, veterinarians should consider the age-dependency of drug pharmacokinetics when drugs, dosages and dosage intervals for treatment of young animals are chosen.     

Effect of toxic hepatitis on pharmacokinetics of salicylate in dogs

The effect of carbon tetrachloride (CT) induced toxic hepatitis on the pharmacokinetics of sodium salicylate was studied in beagle dogs. Plasma concentrationtime profiles were determined for sodium salicylate in ten healthy dogs and in the same dogs after CT administration. Laboratory tests for liver disease were performed before and after liver injury in order to examine the feasibility of using commonly employed laboratory tests as a guide for determining dosage regimens of sodium salicylate in the presence of liver dysfunction. The disappearance of sodium salicylate from the plasma of dogs was a first-order process through 8 h in both the normal and liver disease states. After CT, there was an alteration in the kinetic behavior between 8 and 24 h after salicylate administration. This change was linked to the decreased ability of the damaged liver to form glucuronides. The changes observed in the pharmacokinetics of salicylate before and after CT induced liver dysfunction were minimal and not statistically significant. The majority of the dogs, however, demonstrated a slightly decreased half-life after CT administration. This was due to an increase in the urinary excretion of unchanged salicylate. It was not possible to correlate laboratory parameters with pharmacokinetic parameters. Therefore, dosage alterations could not be based upon laboratory data. Data from this investigation, however, did not suggest the need to routinely alter the dosage of salicylate in the presence of CT induced toxic hepatitis.     

Comparative pharmacokinetics of acetylsalicylic acid and sodium salicylate in chickens and turkeys

1. Pharmacokinetics of acetylsalicylic acid (ASA) and sodium salicylate (SS) were assessed following single intravenous (i.v.) and oral administration at doses of 50 mg/kg body weight to chickens and turkeys. Plasma drug concentrations were determined using high-performance liquid chromatography with ultraviolet detection and pharmacokinetic variables were calculated using a non-compartmental model.

2. The mean residence time (MRT) of salicylate (SA) after i.v. administration of SS was 6.08 ± 0.59 and 3.32 ± 0.27 h and after oral administration was 6.95 ± 0.72 and 4.55 ± 0.71 h in chickens and turkeys, respectively. The elimination half-life (T _{1/2 e}) was shorter in turkeys compared with chickens. The value of body clearance (Cl_B) was higher in turkeys than in chickens, but the apparent volume of distribution (V _ss) was similarly low in both species. The bioavailability of SS was complete and the maximal plasma concentration of SA (C _max) after oral administration was 96.93 ± 8.06 and 91.76 ± 9.64 µg/ml, respectively, in chickens and turkeys.

3. The MRT of ASA after iv administration was 0.24 ± 0.08 and 0.24 ± 0.02 h and after oral administration was 0.78 ± 0.25 and 0.59 ± 0.13 h, respectively, in chickens and turkeys. In both species, T _{1/2 e} was very short, Cl_B and V _ss were similar and markedly higher than those of salicylate. The bioavailability of unchanged ASA was low and C _max after oral administration was 6.9 ± 3.6 µg/ml in chickens and 8.6 ± 1.3 µg/ml in turkeys.     

Biotransformation enzymes as determinants of xenobiotic toxicity in domestic animals

After coming in contact with living organisms, the majority of foreign compounds undergo a number of chemical reactions known as biotransformations. These are performed by hepatic and extra-hepatic enzyme systems and usually yield more polar derivatives, referred to as 'metabolites', which may leave the body via the urinary and biliary routes or be excreted in animal products such as milk and eggs. Biotransformation does not always imply detoxification because in certain instances metabolites will be produced that are capable of reacting with tissue macromolecules or acquiring toxic properties different to or greater than those of the parent molecule.In this review, which is focused on domestic animals, the role played by oxidative, reductive, hydrolytic and conjugative biotransformation enzymes in the activation/detoxification of xenobiotics is examined. The relationship between extra-hepatic metabolism and target organ toxicity as well as the action of rumen microflora on feed additives, phytotoxins, and pesticides are then discussed. Some of the most important metabolic-based species-related susceptibilities to different poisons, and the influence of enzyme inducers or inhibitors on xenobiotic toxicity and drug safety are also reviewed.     

影响水产动物药代动力学的因素

对影响水产动物药代动力学的机体因素、药理因素和环境因素进行了综述。影响药动学的因素很多，尤其对于所处环境因素复杂的水产动物来说，除了遗传种属、性别等生理因素和病理、药理等因素外，环境因子尤其是水温能显著影响药代动力学过程。研究不同条件下的药动学，对于合理、正确地使用药物有重要的指导作用。     

Gentamicin pharmacokinetics in newborn and 42-day-old male piglets

The pharmacokinetics of gentamicin was investigated in six newborn male piglets, aged from 4 to 12 h at the time of administration of the drug, and six 42-day-old castrated male piglets, that had been weaned for 2 weeks following a single intravenous bolus of 5 mg/kg. Gentamicin was measured in serum and in urine by a fluorescence polarization immunoassay. The serum concentrationtime data were best described by a three-compartment open model. A rapid initial distribution phase (± phase) was observed in every animal. The serum β half-life (t_1/2β) was significantly longer in the newborn piglets (mean ± SEM) (5.19 ± 0.30 h) than in the older group (3.50 ± 0.23 h) (P < 0.05). Mean residence time was similarly longer in younger piglets (6.62 ± 0.57 h) than in older animals (2.86 ± 0.11 h) (P < 0.05). The steady-state volume of distribution (V_ills was significantly larger for younger pigs (0.785 ± 0.036 L/kg) than in elder pigs (0.474 ± 0.029 L/kg) (P < 0.05). Urinary γ half-life (t_1/27u) was 72.66 ± 10.78 h in the newborn piglets and 69.20 ± 14.77 h in the 42-day-old animals. A urinary δ phase was observed in three of the 42-day-old piglets and gave a mean (t_1/2δu of 232.01 ± 14.55 h. Percentages of urinary recovery of the administered dose after 144 h were 94.18 ± 1.01 and 94.04 ± 1.12 in the newborn and 42-day-old animals, respectively. Serum gentamicin clearance was significantly lower in younger animals (0.121 ± 0.007 L/h±kg) than in the 42-day-old group (0.166 ± 0.010 L/h·kg). It is suggested that in the newborn piglets, the increase of V_d(ss) could be explained by a higher proportion of extracellular water while the lower clearance could be attributed to a reduced glomerular filtration capacity. Gentamicin dosage requirement in the newborn piglets would therefore have to be adjusted, in order to take into consideration the observed differences in the mean values of these latter pharmacokinetic parameters.     

The influence of rapid growth on sodium salicylate pharmacokinetics in male turkeys

The aim of this study was to assess the influence of growth on the pharmacokinetics of sodium salicylate (SS) in male turkeys. SS was administered intravenously at a dose of 50 mg/kg. Plasma drug concentrations were assessed by high‐performance liquid chromatography, and pharmacokinetic parameters were calculated by noncompartmental analysis. As the age increased from 6 to 13 weeks (body weight increase from 2.35 to 9.43 kg), median body clearance decreased from 1.34 to 0.87 ml/min/kg. This caused a significant increase in the median mean residence time from 3.42 to 4.44 hr. Elimination phase proved to be biphasic and two elimination half‐lives (T_1/2el) were distinguished. Whereas T_1/2el1 was found to increase with age by 128%, T_1/2el2 represented a later but faster and less age‐dependent phase of elimination (increase by 56% in the respective groups). Volume of distribution decreased with age. These effects may lead to different therapeutic response to SS in turkeys of different age and body weights.     

The pharmacokinetics of salicylate in dairy cattle are not altered by simultaneous intravenous ceftiofur sodium and DL-lysine-acetyl salicylate (Aspirin)

This study evaluated potential alterations to the pharmacokinetics of salicylate by concurrently administered ceftiofur sodium. The trial design was a crossover using 10 non-lactating, non-pregnant dairy cows. In the first period each cow received intravenously (IV) 26 mg/kg of DL-lysine acetyl salicylate (aspirin) followed immediately by 2 mg/kg ceftiofur sodium. In the second period each cow received 26 mg/kg of aspirin IV. Plasma samples were harvested for determination of salicylate concentration by HPLC. The data best fitted a single compartment open model, using weighted non-linear regression. No alterations to the pharmacokinetic parameters of salicylate in cattle by concurrently administered ceftiofur sodium were detected ( P <0.05). Using 90% confidence intervals, and testing for changes of > 20%. control values, elimination half-life ( t ₁/₂), apparent volume of distribution ( V _d), area under the plasma concentration versus time curve ( AUC ) and mean residence time ( MRT ) were not altered. For control animals the elimination rate constant ( k _el) and total body clearance ( Cl ) were 1.35/pm0.43 h⁻¹ and 20.2/pm6.1 ml/h.kg respectively (mean/pmSD). Since ceftiofur sodium did not affect the pharmacokinetics of salicylate, dose regimens for aspirin in cattle need not be altered when ceftiofur sodium is administered concurrently.     

Comparative pharmacokinetics of gentamicin, neomycin and oxytetracycline in newborn calves

The pharmacokinetics of three antibiotics--gentamicin, neomycin and oxytetracycline were determined in newborn calves. The kinetic determinations, using two-compartment open models, were made at increasing ages from 1 day to 42 days and compared with those made from older calves (250+ days). Although all three antibiotics are eliminated unchanged primarily by glomerular filtration, there were marked differences in the development of elimination processes for individual drugs. The pharmacokinetics of neomycin were not influenced by age. Although the elimination half-life of gentamicin appeared to decrease with age, the changes were not significant and were due to an increased elimination rate in only one calf. There was no change with age in the remaining three calves. Oxytetracycline elimination was significantly reduced in newborn calves. This was exemplified by a decrease in the half-life of elimination t1/2 (beta) from 672.5 +/- 99.4 in the newborn to 385.6 +/- 76.8 at 6 weeks of age, and 377.3 +/- 40.8 min in the 250-day-old calf. These changes were consistent in all four calves. The rate of elimination remained low for the first 4 weeks of life. The volume of distribution Vd, area was not changed after the first week of life. Based on pharmacokinetic changes, an adjustment of dosage is indicated for oxytetracycline in the newborn calf as compared to the older calf or adult.     

Disposition of sulfonamides in food-producing animals: pharmacokinetics of sulfathiazole in swine

Disposition of sulfathiazole in plasma and urine of swine was determined following single intravenous and oral doses. Pharmacokinetics of the drug were described by a 1-compartment open model. The drug was rapidly eliminated, mainly by renal excretion of unchanged sulfathiazole and metabolism to acetylsulfathiazole, with a biological half-life of 1.4 hours. Sulfathiazole (in solution) was absorbed rapidly (half-life 0.8 hour) and relatively completely (73%) following oral administration.     

Disposition of sulfonamides in food-producing animals: pharmacokinetics of sulfamerazine in cattle

The disposition of sulfamerazine in the plasma and urine of cattle was determined following single intravenous and oral doses. The averaged and the individual animal data were described by a two-compartment pharmacokinetic model. The drug was eliminated with a biological half-life of 6.2 h, primarily by renal excretion of unchanged sulfamerazine and metabolism to acetylsulfamerazine. Sulfamerazine (in solution) was absorbed with a half-life 6.7 h and with relative completeness (68%) following oral administration.     

Disposition of sulfonamides in food-producing animals: pharmacokinetics of sulfamerazine in ewe lambs

Date from plasma and urine samples from four ewe lambs were analyzed after administration of sulfamerazine as single IV and oral doses. A two-compartment pharmacokinetic model was developed to describe the disposition of sulfamerazine. The drug was eliminated, primarily by renal excretion of (i) unchanged sulfamerazine and metabolism to an acetyl metabolite, (ii) polar conjugates, and (iii) a third metabolite. The biological half-life of the drug was 6.6 hours. The average value of the absorption rate constant was 0.433 hour-1 (half-life 1.60 hours). Sulfarmerazine was relatively completely absorbed (approx 81% of dose) after oral administration in solution.     

The pharmacokinetics and effects of intravenously administered carprofen and salicylate on gastrointestinal mucosa and selected biochemical measurements in healthy cats

The pharmacokinetics of carprofen, a propionic acid-derived nonsteroidal anti-inflammatory (NSAID), and its effect on gastrointestinal mucosa, complete blood counts (CBC) and biochemical indicators of liver and renal function were investigated in healthy cats using a randomized crossover design. A single dose of 4 mg/kg of carprofen (Zenecarp(R) Injection), normal saline, or 20 mg/kg of DL-lysine acetyl salicylate (Vetalgine(R)) was given intravenously (i.v.) to each of five cats with a washout period of 2 weeks between treatments. Endoscopy of the stomach and duodenum 8 h postinjection revealed one acetyl salicylate-(aspirin)-treated cat with minor pinpoint erosions. None of the other cats in the three treatment groups had evidence of bleeding or ulceration. Serum biochemistry measurements of blood urea nitrogen (BUN), alanine transferase (ALT) and alkaline phosphatase (ALP) and complete blood counts (CBC) were not significantly altered from pretreatment values by the single dose of salicylate or carprofen (P < 0.05). Early and extended sample time points suggest that the pharmacokinetics of carprofen in the cat fit a 2-compartment model, with a long elimination half-life (t1/2) of 20.1 +/- 16.6 h, an area under the plasma concentration-time curve (AUC) of 637 (+/- 237) microgram.mL/h and a volume of distribution (Vdss) of 0.14 +/- 0.05 L/kg. Intravenously administered aspirin fit a 2-compartment model and had a long elimination half-life (t1/2) of 22.2 +/- 3.1 h, an AUC of 3824.2 +/- 506.7 microgram.mL/h and a volume of distribution (Vdss) of 0.17 +/- 0. 01 L/kg.     

Factors affecting pharmacokinetics of benzimidazole anthelmintics in food-producing animals: the consequences and potential risks

Benzimidazoles are frequently and widely used veterinary anthelmintics. Unfortunately, an administration of these anthelmintics does not always result in the expected therapeutic success. Many host-related factors modify pharmacokinetic behavior and efficacy of a chosen anthelmintic. Pharmacokinetics of anthelmintics varies among animals of different species, sex and age. Also diseases, medication, feed and environmental conditions can significantly affect behavior of anthelmintics and resultant drug efficacy in animals. The presented review gathers information, gained in last 20 years, on factors which bring about the variability in performance of benzimidazole anthelmintics in food-producing animals. It is focused particularly on differences in absorption and metabolism of these anthelmintics as these stages of the pharmacokinetic process seem to be the most important for the overall anthelmintic efficacy. The consequences of abnormalities and alterations in pharmacokinetics of benzimidazole anthelmintics are summarized and discussed.     

Factors affecting pharmacokinetics of benzimidazole anthelmintics in food-producing animals: The consequences and potential risks

Benzimidazoles are frequently and widely used veterinary anthelmintics. Unfortunately, an administration of these anthelmintics does not always result in the expected therapeutic success. Many host-related factors modify pharmacokinetic behavior and efficacy of a chosen anthelmintic. Pharmacokinetics of anthelmintics varies among animals of different species, sex and age. Also diseases, medication, feed and environmental conditions can significantly affect behavior of anthelmintics and resultant drug efficacy in animals. The presented review gathers information, gained in last 20 years, on factors which bring about the variability in performance of benzimidazole anthelmintics in food-producing animals. It is focused particularly on differences in absorption and metabolism of these anthelmintics as these stages of the pharmacokinetic process seem to be the most important for the overall anthelmintic efficacy. The consequences of abnormalities and alterations in pharmacokinetics of benzimidazole anthelmintics are summarized and discussed.     

Use of pharmacokinetics when dealing with the drug residue problem in food-producing animals

If the principal pharmacokinetic parameters of a veterinary drug-such as its elimination half-life from blood plasma, volume of distribution, plasma protein binding and metabolism-are known, then the presence and concentration of residues in animal tissue after administration of the drug can be predicted. This makes it possible to reduce the number of animals required by conventional residue testing and satisfies a legitimate demand of animal welfare groups. Using radioactively labelled drugs, the ratio of the parent substance to its metabolites can be established. Thus as a rule the determination of parent substance is sufficient for the routine determination of residues in foodstuffs. This is true in particular of sulfonamides. The pharmacokinetics of this class of substances are such that their main metabolites are eliminated from the animal's body faster than the parent substance. Other examples given are ceftriaxone, carprofen und climazolam.     

The pathological newborn in small animals: the neonate is not a small adult

The rate of perinatal death is variable but highest during parturition, immediately after birth and in the first days of life. Infectious diseases, above all bacterial, are the second most important cause of mortality after losses during parturition. A lot of factors are involved predisposing puppies and kittens to bacterial infections: respiratory distress, hypothermia, hypoglycaemia, dehydration, congenital abnormalities. E. coli, streptococci and staphylococci, Klebsiella sp., Pseudomonas sp., Enterobacter sp., Proteus sp. and anaerobes are regularly involved in bacterial infections in neonates. Postmortem findings especially document E. coli, Staphylococcus or Streptococcus species as causes of disease and death shortly after birth. The environment and mothers are suspected as sources of infection (vaginal discharge, milk, faeces, oropharynx, skin) for puppies and kittens. Genetic relatedness of bacterial strains in puppies and their mothers was found in staphylococci and E.coli. These results indicate that for repeated cases of bacterial infections in neonates diagnostic procedures of milk, vaginal and faecal swabs from bitches result in isolation of the responsible bacteria with a high probability and suggest that preterm treatment could help to control bacterial diseases and losses in pups.

     

The pathological newborn in small animals: the neonate is not a small adult

The rate of perinatal death is variable but highest during parturition, immediately after birth and in the first days of life. Infectious diseases, above all bacterial, are the second most important cause of mortality after losses during parturition. A lot of factors are involved predisposing puppies and kittens to bacterial infections: respiratory distress, hypothermia, hypoglycaemia, dehydration, congenital abnormalities. E. coli, streptococci and staphylococci, Klebsiella sp., Pseudomonas sp., Enterobacter sp., Proteus sp. and anaerobes are regularly involved in bacterial infections in neonates. Postmortem findings especially document E. coli, Staphylococcus or Streptococcus species as causes of disease and death shortly after birth. The environment and mothers are suspected as sources of infection (vaginal discharge, milk, faeces, oropharynx, skin) for puppies and kittens. Genetic relatedness of bacterial strains in puppies and their mothers was found in staphylococci and E.coli. These results indicate that for repeated cases of bacterial infections in neonates diagnostic procedures of milk, vaginal and faecal swabs from bitches result in isolation of the responsible bacteria with a high probability and suggest that preterm treatment could help to control bacterial diseases and losses in pups.