摘要:

The disposition of rifampin in six healthy mares after single intravenous (i.v.) and oral (p.o.) doses and after seven oral doses of 10 mg/kg administered twice a day was investigated using a high performance liquid chromatographic (HPLC) method. Pharmacokinetic variables for rifampin determined using the HPLC method were comparable to variables reported from earlier studies utilizing a microbiological assay. Desascetylrifampin, a major metabolite of the parent compound, could not be detected in the serum but was detected at low concentrations in urine. Mean trough concentrations of rifampin increased from the first to the second dose of the multiple dose oral study and then remained unchanged through 72 h. At 84 h after the first dose (i.e. 12 h after the final dose) the rifampin concentration was significantly decreased (P= 0.001). The harmonic mean of the half‐life of rifampin decreased significantly from 13.3 h after a single oral dose of 7.99 h after the seventh oral dose. The mean serum protein binding of rifampin over the concentration range of 2–20 μg/ml was 78%. Mean trough serum concentrations of unbound rifampin after multiple oral doses ranged from 0.67 μg/ml at 24 h to 0.40 μg/ml at 72 h. The mean unbound serum rifampin concentration at 84 h (i.e., 12 h after the final dose) was 0.30 μg/ml. Trough concentrations and the 84‐h sample concentration of unbound rifampin exceeded the minimum inhibitory concentration for most gram positive bacterial isolates from horses reported in this study. All organisms with minimum inhibitory concentrations less than 0.125 μg/ml were considered susceptible.Based on the pharmacokinetics of rifampin after p.o. administration, we concur with the current dosage recommendation of 10 mg/kg twice a day by mouth. At this dose, most streptococci,Rhodococcus equi, and coagulase‐positive staphylococci would be considered susceptible

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1993.tb00156.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Fenbendazole (FBZ) was administered intraruminally at 5.0 mg/kg, containing a trace of [14C]‐FBZ, to sheep fitted with a permanent bile duct cannula and the behaviour of FBZ and its metabolites examined in bile and plasma. Of the administered radiolabeled dose, 47% was secreted in bile of which 34% was accounted for as conjugated and 4% as unconjugated (free) metabolites. Hydroxylated oxfendazole (OH.OFZ) was the major biliary metabolite contributing 66%, and hydroxy‐FBZ (OH.FBZ) 27%, of the total metabolites characterized. Small amounts of OFZ and hydroxy FBZ sulphone (OH. FBZ.SO2) were also present in bile. The rapid appearance of OH.OFZ in bile, even before maximum concentrations of OFZ occurred in plasma, indicated that sulphoxidation and hydroxylation was the major route of FBZ metabolism.Following intraduodenal infusion of free biliary metabolites, FBZ and its metabolites rapidly appeared in bile indicating absorption from the small intestine. When conjugated metabolites were infused they continued to appear in bile for a further 15–20 h after cessation of infusion indicating that absorption of hydroxylated metabolites occurred largely after bacterial deconjugation in the large intestine. Approximately 40% of biliary metabolites were estimated to undergo enterohepatic reabsorption but they contributed minimally to the metabolite content in plasma. It is suggested that during the process of recycling, biliary metabolites make substantial contact with parasites in the mucosa of the small and large intestine thereby contributing to the anthelmintic activity o

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1993.tb00157.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Phenylbutazone (PBZ) was administered intravenously as a single dose (10 mg/ kg) to adult male and 1‐day‐, 10‐day‐, 4‐week‐ and 6 week‐old male goats. The plasma concentration of PBZ and its major metabolites oxyphenbutazone (OPBZ) and γ‐hydroxyphenbutazone (γ‐OHPBZ) was measured over time. The elimination half‐life (t½β) of PBZ decreased from 120 h in the 1‐day‐old to 16 h in the adult goats. Although the volume of distribution (Vd) did not change significantly during maturation, the total body clearance (ClB) increased from 2 ml.h‐1.kg‐1in I‐day‐old t o 13 ml.h‐1.kg‐1in the adult goats; the increase was 2‐fold in the first 10 days of life. Oxyphenbutazone was detectable in the plasma of adult and 6‐week‐old goats as early as 15 min after PBZ administration. Its peak concentration occurred at 1.5 h (1.6 μg/ml) in adults and at 6 h (0.95 μg/ml) and 12 h (0.36 μg/ml) in 6‐ and 4‐week‐old goats respectively. The highest plasma concentration of γ‐OHPBZ was achiev

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1993.tb00158.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

It is important to study the development of drug biotransformation enzymes, because from a pharmacological and therapeutic point of view these enzymes are responsible for eliminating most drugs. Their concentration at each age is critical when deciding the dose regimen, particularly in the neonates who are deficient or have very low levels of these enzymes. From a toxicological perspective, the role of these enzymes varies, with some of them being directly responsible for activation of certain chemicals to reactive intermediates with deleterious consequences to the animal. The time course of appearance of these enzymes throughout the life of the animal could be depicted from the study of their ontogeny and therefore the prediction of when the animal would be at risk should be possible. Experiments were designed to measurein vitro, the activity of drug‐metabolizing enzymes in liver, lung and kidney of newborn, 1‐week‐, 4‐week and 6‐week‐old and adult goats. The microsomal mono‐oxygenase activities were measured utilizing substrates designed to characterize the development of the cytochrome P450 (P450). For phase II enzymes, the activity of UDP‐glucuronyltransferase towards 1‐naphthol and p‐nitrophenol was measured in addition to the cytosolic glutathione S‐transferase activity towards, 1,2‐dichloro 3‐nitrobenzene. The results indicated that the newborn goat tissues exhibited very low activity of drug‐metabolizing capacity in all pathways studied. These activities increased to the adult values by 6 weeks of age. In general, the development of the mono‐oxygenase activities followed the same pattern as the overall P450. The UDP‐glucuronyltransferase activity towards both substrates was deficient at birth and surged to above adult values by the first week of age. The toxicologic and pharmacologic implications of the development of these

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1993.tb00159.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The effect of gonadal hormones on the plasma elimination and urinary metabolite profile of antipyrine was studied in dwarf goats. Female goats were treated with testosterone and male goats were treated with 17β‐oestradiol. Castrated males were treated with either testosterone or 17β‐oestradiol. Antipyrine (25 mg/kg, i.v.) was given both before and after the hormonal treatments. The effects of the hormonal status on the plasma elimination of the parent compound were not consistent. This was possibly due to the fact that formation of the main metabolite of antipyrine in the goat, 4‐hydroxy antipyrine (OHA), was not affected by sex or hormonal treatment. On the other hand, there were clear effects of hormonal status on urinary excretion of the three other metabolites. In females and castrated males testosterone suppressed the formation of norantipyrine (NORA), 3‐hydroxymethylantipyrine (HMA) and 4,4′‐dihydroxyantipyrine (DOHA). Intact males produced smaller amounts of these metabolites than females. It is concluded that distinct xenobiotic metabolizing pathways exist in the dwarf goat, which are influenced in their activity by gonadal hormones. This confirms previous findings in rats and mice. The possibility that sex hormones influence drug metabolism in food‐producing animals could have consequences for veterinary therapeutics and public health. This study also demonstrates that, when using the antipyrine test for the assessment of hepatic drug metabolism, it is very important to include the determination

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1993.tb00160.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

In 40 experiments on 20 pigs three different organophosphorus insecticides (OPs), parathion (n= 6), phoxim (n= 7) and phosmet (n= 7), were administered both intravenously (i.v.) and dermally (d.) as ‘pour‐ons’ in a crossover design in order to determine the dermal bioavailability of the OPs. As percutaneous absorption of drugs may be affected by the vehicle used, three chemically different vehicles – DMSO, 1‐octanol and macrogol 400 – were used for the dermal administration of each of the OPs. The pharmacokinetic parameters measured showed that 15–30% of dermally applied parathion is absorbed when administered in DMSO or octanol, but only 4–5% when administered in macrogol. Absorption was fastest with DMSO and slowest with macrogol. For the two ectoparasiticides, phoxim and phosmet, only between 0.5 and 3% of the dermal dose was absorbed with little difference in the absorption rate between the three vehicles. On the basis of the very limited dermal bioavailability for these two OPs it seems doubtful whether sufficient concentrations can reach the ectoparasites through the

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1993.tb00161.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Flunixin meglumine was administered intravenously and intramuscularly in sheep and the pharmacokinetics of the drug studied. Plasma concentrations of flunixin were measured by high performance liquid chromatography. The decline in plasma‐ flunixin concentration with time was best fitted by a triexponential equation. The pharmacokinetics following intravenous administration of 1.0 mg/kg indicate that flunixin has a rapid distribution half‐life (t½π= 2.3 min), a slow body clearance rate (Clb= 0.6 ml/kg/min) and an elimination half‐life of 229 min. Similarly, at 2.0 mg/kg, flunixin is rapidly distributed from the plasma, t½π= 2.7 min, has a slow body clearance rate (C/b = 0.7 mk/lg/min) and an elimination half‐life of 205 min.Following intramuscular injection flunixin is rapidly and well absorbed from the injection site. It had a mean maximum concentration (Cmax) of ≫5.9 μg/ml when administered at a dose rate of 1.1 mg/kg, and a relative bioavailability of 70%. Plasma concentrations increase proportionally to dose over the range 1.1 mg/kg‐2.2 mg/kg when administered by the int

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1993.tb00162.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Fenbendazole was administered orally without food to six beagle dogs at 2.5, 5.0, 10, 20, 40 and 80 mg/kg of body weight. Increasing the dose rate did not significantly increase the amount of fenbendazole absorbed. In a separate study fenbendazole was administered to the same six beagle dogs at a dose rate of 20 mg/kg of bodyweight in food with high, medium and low fat content. The food provided 1.52, 0.70 or 0.34 g of fat per kg of body weight. Administration of fenbendazole in food with different fat contents did not affect its relative bioavailability. Administration of fenbendazole at a dose rate of 20 mg/kg in food, irrespective of fat content, did however significantly increase its bioavailability when compared to administration of the same dose as a bolus on an empty stomach.

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1993.tb00163.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The cardiovascular and respiratory parameters of eight laboratory beagles were measured before and after the simultaneous injection of medetomidine (40/iglkg bw) and ketamine (5 mg/bg bw). This combination produced a significant alteration in cardiovascular function. The heart rate, the stroke volume and cardiac output decreased while the systemic vascular resistance increased. These effects were attributed principally to the a2agonist compound combined with the moderate stimulatory effect of ketamine. The respiratory parameters were little affected by this protocol.

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1993.tb00164.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The vasoconstrictor effects of phenylephrine and histamine were investigated in isolated strips of pulmonary arteries in pigs during ageing. Interactions between phenylephrine‐induced responses and arachidonic acid derivatives were also studied by incubating the blood‐vessels with indomethacin. Potency (pD2 values) and maximal effects (Emaxx) recorded in 5‐week‐old piglets (group I,n= 5) with phenylephrine [5.71 ± 0.17 and 0.76 ± 0.22 g/mg of dry tissue respectively (mean ± SEM)] were similar to values found in 12‐week‐old animals (group 2,n =5) (5.49 ± 0.30 and 1.06 ± 0.27 g/mg of dry tissue respectively). The sensitivity and responsiveness of tissues to this agonist were significantly reduced in 26‐week‐old mature pigs (group 3,n =6) as indicated by the decrease in pD2 (3.91 ± 0.23;P<0.01) and Emax(0.27 ± 0.13 g/mg of dry tissue;P<0.05) values observed in this group. Histamine (10_3M)‐induced maximal responses (Emax) were significantly higher in group 2 (2.23 ± 0.49 g/mg) than in group 1 (0.85 ± 0.11 g/mg;P<0.05) and in group 3 (0.48 ± 0.10 g/mg;P<0.01). In 5‐week‐old animals, indomethacin (3.10˜5M) significantly (P<0.05) shifted the concentration‐response curve to phenylephrine to the right (0.28 log. units) and depressed contractions to this drug as shown by the significant decrease of 39.5% (P<0.05) in Emax. This cyclo‐oxygenase inhibitor had no effect in other groups. These data indicate that phenylephrine is a potent and effective vasoconstrictor agent for the main pulmonary arteries in 5‐week‐old piglets and that alpha‐1‐adrenergic‐induced contractions are enhanced by cyclo‐oxygenase products. These findings can be related with the high reactivity of pu

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1993.tb00165.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY