Pharmacokinetic aspects of penicillins,aminoglycosides and chloramphenicol in birds compared to mammals. A review

Summary

Based on a review of the literature, a comparison is made of the pharmacokinetics of penicillins, aminoglycosides, and chloramphenicol in birds and mammals.

Penicillins in birds are likely to be more dependent for their elimination on biotransformation than in mammals. Amoxycillin had a relatively low availability (0.34) after p.o. administration. Higher doses (2 to 8 times) were needed to achieve the same peak levels in birds and mammals.

Aminoglycosides, which for their elimination largely depend on renal excretion by glomerular filtration, show only minor differences in pharmacokinetics between birds and mammals.

Chloramphenicol is mainly excreted after biotransformation and large differences in pharmacokinetic parameters are to be found, not only between birds and mammals, but also between avian species.     

Echocardiographic examinations in unsedated racing pigeons (Columbia livia forma domestica) with special consideration for the physical training

The heart of the bird is characterized by its enormous efficiency. Racing pigeons are bred for a long time for their flight performance. In the present study therefore the heart of 108 racing pigeons of the breed Bricoux were examined by means of echocardiography. The birds were either kept in aviaries (untrained) or as racing birds. The aim was to find out whether differences in the heart dimensions and/or the heart work occur between untrained and trained birds, like it is described already in humans and mammals (so-called athletic's heart). Significant differences between the two groups could be determined with different parameters, in particular with parameters, which affect the heart work. Thus it was for the first time possible to prove the formation of a athletic's heart in birds, and by that the adaptation of the avian heart to appropriate performance requirements.     

Neuroendocrine mechanism of seasonal reproduction in birds and mammals

In temperate zones, animals use changes in day length as a calendar to time their breeding season. However, the photoreceptive and neuroendocrine mechanisms of seasonal reproduction are considered to differ markedly between birds and mammals. This can be understood from the fact that the eye is the only photoreceptive organ, and melatonin mediates the photoperiodic information in mammals, whereas in birds, photoperiodic information is directly received by the deep brain photoreceptors and melatonin is not involved in seasonal reproduction. Recent molecular and functional genomics analysis uncovered the gene cascade regulating seasonal reproduction in birds and mammals. Long day‐induced thyroid stimulating hormone in the pars tuberalis of the pituitary gland regulates thyroid hormone catabolism within the mediobasal hypothalamus. Further, this local thyroid hormone catabolism appears to regulate seasonal gonadotropin‐releasing hormone secretion. These findings suggest that although the light input pathway is different between birds and mammals (i.e. light or melatonin), the core mechanisms are conserved in these vertebrates.     

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.     

Atipamezole increases medetomidine clearance in the dog: an agonist—antagonist interaction

Medetomidine, an α₂-adrenoceptor agonist, is a potent sedative and analgesic agent in the dog. When necessary, its action can be effectively antagonized by atipamezole. The present work was designed to study the effects of these drugs on each others' pharmacokinetics when a single intramuscular dose of medetomidine (50 μg kg^-1) was followed by a dose of atipamezole (250 μg kg^-1). Three different treatments were used: medetomidine alone, atipamezole alone, and atipamezole after medetomidine. Drug concentrations in plasma were measured by GC-MS. Statistical analysis of the results (anova) revealed significant differences between treatments in the kinetic parameters of medetomidine. Atipamezole decreased the AUC of medetomidine from 41.3 to 28.6 ng h ml"¹(P = 0.005), t_1/4 from 1.44 to 0.87 h ( P = 0.015), and increased Cl from 21 to 31 ml min^-1kg^-1(P = 0.017). Differences in V₂ did not reach statistical significance. The only statistically significant effects of medetomidine on the pharmacokinetics of atipamezole in this study were the slight decrease of Cl and C _max as well as the increase of AUC . It is suggested that the large dose of medetomidine used caused haemodynamic changes, resulting in decreased hepatic circulation and slower drug metabolism. Antagonism by atipamezole restored the hepatic blood flow and, consequently, increased the elimination of medetomidine by biotransformation.     

Interspecies variations in plasma half-life of ampicillin, amoxycillin, sulphadimidine and sulphacetamide related to variations in body mass.

The relationships between the half-lives during the elimination phase (t1/2 minutes) of ampicillin, amoxycillin, sulphadimidine and sulphacetamide and body mass (W, kg) between species of mammals and birds were examined using data from the authors' experiments and collected from the literature. Linear regression of the log half-lives of ampicillin, amoxycillin and sulphadimidine following intravenous injection on the log body mass for a variety of species of mammals and birds revealed significant correlations (r = 0.7709, n = 8, r = 0.7712, n = 8, r = 0.7749, n = 10). The interspecies relationships were described by the allometric equations t1/2 = 31.3 W0.16, t1/2 = 32.7 W0.12 and t1/2 = 129.2 W0.28, respectively. These equations may be of value for estimating dose intervals in species for which no relevant pharmacokinetic data are available.     

Pharmacokinetics in immature animals: a review.

Differences in drug pharmacokinetics between newborn and adult mammals are reviewed. The pharmacokinetic alterations during the maturation process are related to changes in the pattern of absorption, distribution, metabolism, and renal excretion. The most pronounced feature in neonates vs adults is the prolonged elimination half-life of drugs. The main factors causing delayed elimination are under-developed renal clearance and immature metabolism of drugs. Special attention has to be paid to central nervous system depressants and to drugs that are extensively metabolized because they will accumulate with repeated dosing of newborn animals.     

Pharmacokinetics of voriconazole after oral administration of single and multiple doses in African grey parrots (Psittacus erithacus timneh)

OBJECTIVE: To determine the pharmacokinetics and safety of orally administered voriconazole in African grey parrots. ANIMALS: 20 clinically normal Timneh African grey parrots (Psittacus erithacus timneh). PROCEDURES: In single-dose trials, 12 parrots were each administered 6, 12, and 18 mg of voriconazole/kg orally and plasma concentrations of voriconazole were determined via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) was administered orally to 6 birds every 12 hours for 9 days; a control group (2 birds) received tap water. Treatment effects were assessed via observation, clinicopathologic analyses (3 assessments), and measurement of trough plasma voriconazole concentrations (2 assessments). RESULTS: Voriconazole's elimination half-life was short (1.1 to 1.6 hours). Higher doses resulted in disproportional increases in the maximum plasma voriconazole concentration and area under the curve. Trough plasma voriconazole concentrations achieved in the multiple-dose trial were lower than those achieved after administration of single doses. Polyuria (the only adverse treatment effect) developed in treated and control birds but was more severe in the treatment group. CONCLUSIONS AND CLINICAL RELEVANCE: In African grey parrots, voriconazole has dose-dependent pharmacokinetics and may induce its own metabolism. Oral administration of 12 to 18 mg of voriconazole/kg twice daily is a rational starting dose for treatment of African grey parrots infected with Aspergillus or other fungal organisms that have a minimal inhibitory concentration for voriconazole < or = 0.4 microg/mL. Higher doses may be needed to maintain plasma voriconazole concentrations during long-term treatment. Safety and efficacy of various voriconazole treatment regimens in this species require investigation.     

Identification and characterization of the enzymes responsible for the metabolism of the non‐steroidal anti‐inflammatory drugs,flunixin meglumine and phenylbutazone,in horses

The in vivo metabolism and pharmacokinetics of flunixin meglumine and phenylbutazone have been extensively characterized; however, there are no published reports describing the in vitro metabolism, specifically the enzymes responsible for the biotransformation of these compounds in horses. Due to their widespread use and, therefore, increased potential for drug–drug interactions and widespread differences in drug disposition, this study aims to build on the limited current knowledge regarding P450‐mediated metabolism in horses. Drugs were incubated with equine liver microsomes and a panel of recombinant equine P450s. Incubation of phenylbutazone in microsomes generated oxyphenbutazone and gamma‐hydroxy phenylbutazone. Microsomal incubations with flunixin meglumine generated 5‐OH flunixin, with a kinetic profile suggestive of substrate inhibition. In recombinant P450 assays, equine CYP3A97 was the only enzyme capable of generating oxyphenbutazone while several members of the equine CYP3A family and CYP1A1 were capable of catalyzing the biotransformation of flunixin to 5‐OH flunixin. Flunixin meglumine metabolism by CYP1A1 and CYP3A93 showed a profile characteristic of biphasic kinetics, suggesting two substrate binding sites. The current study identifies specific enzymes responsible for the metabolism of two NSAIDs in horses and provides the basis for future study of drug–drug interactions and identification of reasons for varying pharmacokinetics between horses.     

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.     

Pharmacokinetics of sulphobromophthalein, lidocaine and indocyanine green in the course of subclinical fascioliasis in sheep

The pharmacokinetics of three drugs proposed for the assessment of liver function: sulphobromophthalein (BSP), lidocaine and indocyanine green (ICG) were determined in sheep four, eight, 12, 16 and 24 weeks after their infestation by an oral administration of 150 metacercariae of Fasciola hepatica. The disposition of BSP was altered by a significant decrease in its total plasma clearance from eight weeks after infection onwards. This change could be related to the low values of the elimination rate constant consistent with a reduced liver cytosolic conjugation of the dye to glutathione. Lidocaine pharmacokinetics were unaffected by parasitism and the only effect on ICG was an increased volume of distribution consistent with the liver hypertrophy caused by the subclinical fascioliasis.     

Pharmacokinetics and tissue residues of kitasamycin in healthy and diseased broilers

The pharmacokinetics of kitasamycin after intravenous and oral administration in a dose of 300 mg/kg b.wt. was studied in 18 healthy and 18 Salmonella gallinarum naturally infected chickens. The tissue residue of the studied antibiotic was estimated in 36 normal chickens when it was given orally for 7 successive days. Therapeutic level of kitasamycin was achieved after 15 minutes and persisted for 20-22 hours after its oral administration. Higher serum kitasamycin concentrations were recorded in Salmonella gallinarum infected chickens. The elimination half-life of kitasamycin calculated after single intravenous injection was 9.03 hours in diseased chickens corresponding to 3.74 hours in healthy birds. The body clearance was significantly reduced in diseased chickens (23.86 ml/kg/min) when compared to that in normal ones (62.03 ml/kg/min). Kitasamycin treated broilers should not be slaughtered before 3 days from the last dose as it was detected only in bile and caecum at that time but not in edible tissues.     

A MYELOGRAPHIC TECHNIQUE FOR AVIAN SPECIES

A post-mortem myelogram was used to diagnose a vertebral fracture in a Red-tailed Hawk ( Buteo jamaicenis ). This diagnosis led the authors to believe that myelography would be useful in live birds. In a pilot study using live adult female chickens (Gallus domesticus) , mammalian myelographic techniques were modified for avian anatomic differences. A thoracolumbar puncture site was used rather than the lumbar or cisternal site which is commonly used in mammals. The volume of contrast medium needed to produce a diagnostic myelogram in birds(0.8–1.2 ml/kg) was found to be approximately four times that needed in mammals. A 25 gauge spinal needle was used rather than a 23 gauge needle. Myelograms of diagnostic quality were obtained with normal subject recovery. Seizures, the most common post-myelographic complication in mammals, were not observed in any of the birds studied. Avian myelography was found to be a cost effective and humane technique with potential application to avian practice.     

How to succeed as a virus: strategies for dealing with the immune system

Viruses may be viewed as genetic information whose success depends on avoiding elimination from individual hosts, or, if this is not possible, in persisting in the population of their hosts. The immune system represents the crucial defense mechanism responsible for the elimination of viruses from individual hosts and for the establishment of immunity that prevents a recurring infection by the same virus. Herd immunity, i.e., immunity of the population against infection resulting from the immunity of a certain fraction of the individuals of the population, represents an important concept in the interaction of viruses with their hosts. Thus, if the number of susceptible hosts decreases below a critical threshold, viruses may risk extinction because they literally run out of substrate. This possibility is increased due to the viruses' low resistance to inactivation outside their hosts by physical influences, such as heat and ultraviolet radiation. Some viruses have adopted a strategy of dual host tropism, i.e., they may reside in reservoir hosts that permit them to survive for extended periods of times. Examples of such viruses are the large and taxonomically diverse group of arboviruses. Moreover, although not normally discussed under this aspect, influenza viruses can also be said to have adopted this strategy, in view of water fowl representing reservoir hosts from which complete viruses may directly cross over to mammals, as was the case with the equine Jilin (Guo et al., 1995) or, more recently, the H5 subtype of influenza virus in humans (Shortridge et al., 1998). In addition, influenza viruses of birds may be transmitted, albeit only partially, through genetic reassortment (Shu et al., 1996).     

Evaluation of the effects of dietary n-3 fatty acid supplementation on the pharmacokinetics of doxorubicin in dogs with lymphoma

OBJECTIVE: To determine the effect of dietary n-3 fatty acids on the pharmacokinetics of doxorubicin in dogs with lymphoma. ANIMALS: 23 dogs with lymphoma in stages IIIa, IVa, and Va. PROCEDURE: Dogs receiving doxorubicin chemotherapy were randomly allocated to receive food with a high (test group) or low (control group) content of n-3 fatty acids. Serum doxorubicin and doxorubicinol concentrations were measured via high-performance liquid chromatography before and 6 to 9 weeks after initiation of the diets. Lymph node concentrations of doxorubicin were assessed 6 hours after the initial treatment. Dogs' body composition was assessed by means of dual-energy x-ray absorptiometry scans. RESULTS: No significant differences in doxorubicin pharmacokinetics were detected between treatment groups. Significant differences existed between the first and second sampling times among all dogs for area under the curve, maximum serum concentration, and clearance. Differences in body composition did not affect measured pharmacokinetic variables. The terminal elimination half-life was longer in dogs in which a long-term remission was achieved than in dogs that did not have remission. CONCLUSIONS AND CLINICAL RELEVANCE: Dietary supplementation of n-3 fatty acids is common in veterinary patients with neoplasia, but supplementation did not affect doxorubicin pharmacokinetics in this population of dogs. Explanations for the beneficial effects of n-3 fatty acids other than alterations in the pharmacokinetics of chemotherapy drugs should be investigated. Dogs may metabolize drugs differently prior to remission of lymphoma than when in remission. The pharmacokinetics of doxorubicin at the time of the first administration may predict response to treatment.     

Comparison of the pharmacokinetics of five aminoglycoside and aminocyclitol antibiotics using allometric analysis in mammal and bird species

The allometric equations relating the half-life, the volume of distribution and the total body clearance of gentamicin, amikacin, tobramycin, kanamycin and apramycin to body weight for mammalian and mammalian + avian species were defined. Literature data were used as a source of comparative pharmacokinetic data. For all antibiotics examined half-life intercepts ranged from 0.49 to 1.66, slopes from 0.05 to 0.45, volume of distribution intercepts--0.13-0.75, slope-- 0.77-1.41, total body clearance intercepts--0.88-8.8 and slope--0.62-1.04. A better relationship between pharmacokinetic parameters and body weight was shown when all values were included in the allometric analysis. Different values of intercept and slope between birds and mammals were found in gentamicin and apramycin studies. In some cases, slopes and intercepts changed when all values of pharmacokinetic parameters were included. We conclude that small difference exist between pharmacokinetics of gentamicin, amikacin, tobramycin, kanamycin and apramycin. The allometric equations shown in our study provide a basis to estimate dose intervals for mammals and birds for which specific information is lacking.     

Intravenous pharmacokinetics of penicillin G and antipyrine in ostriches (Struthio camelus) and emus (Dromaius novaehollandiae).

Penicillin G and antipyrine, which served as model drugs to assess the relative capacities of renal and hepatic elimination pathways, respectively, were each administered intravenously to six ostriches (Struthio camelus) and to six emus (Dromaius novaehollandiae). Drug concentrations in blood samples collected over a period of 12 hr after administration were assayed, and elimination half-life, mean residence time, clearance, and steady-state volume of distribution were calculated. Mean values for elimination half-life and mean residence time of penicillin G were significantly higher in emus than in ostriches; no significant differences in antipyrine pharmacokinetics between species were demonstrated.     

Comparative Pharmacokinetics and Bioavailability of Amoxycillin in Chickens after Intravenous,Intramuscular and Oral Administrations

The pharmacokinetics and systemic bioavailability of amoxycillin were investigated in clinically healthy, broiler chickens (n = 10 per group) after single intravenous (i.v.), intramuscular (i.m.), and oral administrations at a dose of 10 mg/kg body weight. The plasma concentrations of amoxycillin were determined using high-performance liquid chromatography (HPLC) and the data were subjected to compartmental and non-compartmental kinetic analyses. Following single i.v. injection, all plasma amoxycillin data were described by a two compartment-open model. The elimination half-lives of amoxycillin were 1.07 h, 1.09 h and 1.13 h after single i.v., i.m. and oral administration, respectively. The total body clearance (Cl(B)) of amoxycillin was 0.80 (L/h)/kg and the volume of distribution calculated as V(d(area)) was 1.12 L/kg, respectively after i.v. administration. Substantial differences in the resultant kinetic data were obtained by comparing the plasma concentration profiles after i.m. injection with that after oral administration. The systemic i.m. bioavailability of amoxycillin was higher (77.21%) than after oral (60.92%) dosing. In vitro, the mean plasma protein binding of amoxycillin amounted to 8.27%. Owing to high clearance of amoxycillin in birds in our study, a plasma level was maintained above 0.25 microg/ml for only 6 h after i.m. and oral routes of administration and consequently frequent dosing may be necessary daily.     

Amoxicillin pharmacokinetics in harbor seals (Phoca vitulina) and northern elephant seals (Mirounga angustirostris) following single dose intravenous administration: implications for interspecific dose scaling

The pharmacokinetics of sodium amoxicillin after a single intravenous dose of 20 mg/kg were determined in ten harbor seals (Phoca vitulina) and ten northern elephant seals (Mirounga angustirostris). The seals ranged in age from 1 to 6 months and the mean weights were 11.7 kg (range, 9.5-18.5 kg) for harbor seals and 47.1 kg (range, 39.5-61.4 kg) for elephant seals. The median half-life of amoxicillin (quartiles) in harbor seals, 1.5 (1.0-3.1) h. was not statistically different from that of elephant seals, 2.0 (1.4-3.8) h, nor were the differences between the terminal elimination rate constants between the two species. The only statistically significant differences between species were for area-under-the-curve (AUC), and total systemic clearance. The lack of statistical significance for differences in the volume of distribution at steady-state (Vss) may have been due to minor differences in the time frame of data collection and dose administered between the two groups. A true physiologic difference in drug handling, possibly related to renal perfusion or tubal secretory efficiency could affect amoxicillin kinetics in these species, and longer administration intervals may be appropriate for elephant seals as compared to harbor seals when administering multiple dose amoxicillin therapy at 20 mg/kg.     

Reversal of medetomidine-induced sedation in reindeer (Rangifer tarandus tarandus) with atipamezole increases the medetomidine concentration in plasma

The pharmacokinetics of two potent α₂-adrenoceptor agents that can be used for immobilization (medetomidine) and reversal (atipamezole) of the sedation in mammals, were studied in three reindeer ( Rangifer tarandus tarandus) in winter and again in summer. Medetomidine (60 μg/kg) was injected intravenously (i.v.), followed by atipamezole (300 μg/kg) intravenously 60 min later. Drug concentrations in plasma were measured by HPLC. The administration of atipamezole resulted in an immediate 2.5–3.5 fold increase in the medetomidine concentration in plasma. Clearance for medetomidine (median 19.3 mL/min·kg) was lower than clearance for atipamezole (median 31.0 mL/min·kg). The median elimination half-lives of medetomidine and atipamezole in plasma were 76.1 and 59.9 min, respectively. The animals became resedated 0.5–1 h after the reversal with atipamezole. Resedation may be explained by the longer elimination half-life of medetomidine compared to atipamezole.