Absorption, distribution, metabolism, and excretion of dirlotapide in the dog

Three once-daily oral doses of 0.2 mg/kg [¹⁴C]dirlotapide were administered to beagle dogs to study the absorption, distribution, metabolism, and excretion of dirlotapide. Mean ¹⁴C recovered at 2.5 and 4.5 h after the last dose was 90%. Mean ¹⁴C in urine, bile, and feces was <1%, 1.7%, and 56% of the dose, respectively. In tissues, 26% of the ¹⁴C dose was present in the gastrointestinal tract, 6.0% in liver, and <1% each in kidney, gall bladder, heart, and brain. To further characterize drug disposition, a single 2.5-mg/kg oral dose of [¹⁴C]dirlotapide was administered to beagle dogs. More than 84% of the dose had been eliminated by 72 h in feces, with 21% of the dose present in feces as parent dirlotapide. Less than 1% of the dose was excreted in urine. In bile collected during the first 24-h postdose from three dogs, 32% and 11% of the ¹⁴C dose was present in samples from male and female dogs, respectively. Based upon metabolite profiling of plasma, excreta, and bile samples, dirlotapide was extensively metabolized to more than 20 metabolites. Biliary/fecal excretion and the potential for enterohepatic recycling of metabolites are suggested.     

Absorption and metabolism of alpha-ketoglutarate in growing pigs

The portal appearance of enteral alpha-ketoglutarate (AKG) and the effect of enteral or parenteral AKG on portal net appearance of glucose, short-chain fatty acids, alanine, aspartate, glutamate, glutamine, proline and insulin were investigated in three growing pigs. During the experimental samplings the pigs were fed hourly with a standard feed mix with 5% glucose (control), 5% AKG (enteral) or no feed additive but continuously infused with AKG into the mesenteric vein in an amount equivalent to 5% of feed intake (parenteral). The arterial plasma concentration of AKG increased (p < 0.05) following both enteral (from 16+/-2 to 22+/-3 micromol/l) and parenteral (from 16+/-2 to 425+/-27 micromol/l) administration of AKG. With the enteral treatment 4+/-1% of the AKG could be accounted for in the portal vein, however, with the parenteral treatment 86+/-5% could be accounted for in the portal vein. The arterial plasma concentration of proline increased (p < 0.05) with the enteral treatment (365 +/- 3 to 443 +/- 39 micromol/l), but was not affected by the parenteral treatment (p > 0.10). The plasma concentration glutamine decreased (p < 0.05) with the parenteral treatment only. The portal net appearance of proline showed a numerical increase with the enteral treatment but no other affects on arterial concentrations or portal net appearance were found. A small accompanying study showed that only small amounts of enteral AKG was present in the small intestine. It was therefore concluded that enteral AKG has a low availability to peripheral tissues either because it is absorbed and metabolized in the stomach and duodenum or because it is metabolized by microbes in the stomach. The study showed that AKG is metabolized differently following enteral and parenteral application in growing pigs.     

Sulfatroxazole: pharmacokinetics, metabolism and urinary excretion in goats and pigs

The disposition of sulfatroxazole (STZ) has been studied in goats and pigs after intravenous administration of a single dose. The percentage of protein-binding decreased with increasing plasma concentration in both species. At 100 micrograms/ml about 85% was bound to plasma proteins in goats, while the corresponding value was only 55% in pigs. Two metabolites of STZ were isolated from urine and identified as N4-acetyl-STZ and 3-sulfanilamido-4-methyl-5-hydroxy-methyl-isoxazole (5'-OH-STZ). The goats excreted about 80% of the dose in urine. The majority (64%) was excreted as unchanged STZ, while N4-acetyl-STZ and 5'-OH-STZ made up 19% and 18%, respectively. The pigs excreted 95% of the dose in urine. Unchanged STZ amounted to 30% and N4-acetyl-STZ to 70% of the urinary excretion in pigs, while there were only traces of 5'-OH-STZ.     

Renal excretion of N4-acetyl sulphanilamide and N4-acetyl sulphadimidine in goats

The renal excretion of N⁴-acetyl sulphanilamide and N⁴-acetyl sulphadimidine was studied in 19 experiments with 6 goats during continuous intravenous administration of the 2 sulphonamide derivatives. Deacetylation of both compounds takes place to a small extent only. Further it is shown that both sulphonamide derivatives are bound to plasma proteins to a greater extent than sulphanilamide and sulphadimidine. The excretion of the N⁴-acetylated sulphonamides is compared with the renal excretion of creatinine. The non-protein-bound fraction of the 2 N⁴-acetylated sulphonamides is excreted by filtration and active tubular secretion. The renal clearances of the acetyl derivatives are higher than those of the parent compounds.     

Absorption and metabolism of estrogens from the stomach and duodenum of pigs

To determine the absorption and metabolism of 17β-estradiol (E₂) by the stomach and liver of the pig, crystalline E₂ was placed in the stomach of prepubertal gilts. Blood samples were subsequently obtained from the hepatic portal and jugular veins and plasma was assayed for E₂, estrone (E₁), 17β-estradiol-glucuronide (E₂G), estrone-glucuronide (E₁G) and estrone-sulfate (E₁S). Concentrations of E₂, E₁, E₂G and E₁S rose in the hepatic portal vein within five min and remained elevated for several hr. Concentration of E₂ represented only 6% of the total estrogen detected in the hepatic portal vein during the sampling period, indicating that most of the E₂ was converted or conjugated prior to entering the hepatic portal vein. The metabolism of E₂ presumably occurred in the stomach mucosa because food had been withheld for 26 hr before infusion of E₂. Concentrations of E₂G, E₁G and E₁S, but not E₂ and E₁, rose in the jugular vein and remained elevated for several hr. The lack of a rise in E₂ and E₁ in the jugular vein indicates that the E₂ and E₁ from the hepatic portal vein were completely converted and/or removed by the liver. Most of E₂ was converted to E₁ and then to E₁G. The infusion of bile containing normal estrogens from pregnant gilts into the duodenum of prepubertal gilts resulted in a peak of E₁G and E₂G in the hepatic portal and jugular veins within a few minutes. This was followed in about 180 min by a second sustained rise. The first peak was essentially abolished by extracting E₁ and E₂ from the bile before infusion. The second peak failed to occur in gilts given antibiotics orally to reduce gut bacteria before infusion of bile.     

Absorption, distribution, and excretion of imidocarb dipropionate in sheep

Spectrophotometric and thin-layer chromatographic methods for determination of imidocarb in biological specimens are described. Following intravenous injection of imidocarb (2.0 mg/kg) into 3 sheep, plasma concentrations, initially averaging 10.8 microgram/ml, decreased to an average of 1.9 microgram/ml within 1 hour and then to less than 1 microgram/ml within the next 4 hours. When imidocarb (4.5 mg/kg) was injected intramuscularly (IM) into 7 sheep, peak plasma concentrations averaging 7.9 microgram/ml were achieved within 4 hours and then rapidly decreased to 4.6 microgram/ml within the next 2 hours. Plasma values then decayed very slowly by first-order kinetics and trace amounts were still present 4 weeks after treatment. Imidocarb was bound to plasma proteins and the apparent volume of distribution was estimated to be slightly higher than the total body water. The concentrations of the drug in the plasma and in the erythrocytes were approximately equal. Detectable amounts were present in all examined tissues 4 weeks after IM administration Twenty-four hours after IM administration, the highest concentrations were in kidney, liver, and brain. The 14C-labeled imidocarb could be detected in all regions of the central nervous system examined, in the hypophysis, and in the pineal body. Metabolic or biotransformation products were not detected by the methods used. Of the administered IM dose, 11 to 17% was excreted in the urine within 24 hours; thereafter, the excretion rate was low, and detectable amounts were still present in the urine for 4 weeks. Renal clearance of imidocarb was less than glomerular filtration rate, indicating net tubular reabsorption. The relatively high concentration of imidocarb in the bile suggests that the bile is an important route of excretion. High concentrations were also found in the mild of lactating ewes, but the drug could not be detected in the plasma of lambs fed milk from these ewes.     

Pharmacokinetics, renal clearance, tissue distribution, and residue aspects of sulphadimidine and its N4-acetyl metabolite in pigs

Pharmacokinetics and tissue distribution experiments were conducted in pigs to which sulphadimidine (SDM) was administered intravenously, orally, and intramuscularly at a dosage of 20 mg SDM/kg. SDM was acetylated extensively, but neither hydroxy metabolites nor their derivatives could be detected in plasma, edible tissues or urine. Following i.v. and two oral routes of administration, the N4-acetylsulphadimidine (N4-SDM) concentration-time curve runs parallel to that of SDM. The percentage of N4-SDM in plasma was in the range between 7 and 13.5% of the total sulphonamide concentration. The bioavailability of SDM administered in a drench was 88.9 +/- 5.4% and administered mixed with pelleted feed for 3 consecutive days it was 48.0 +/- 11.5%. The renal clearance of unbound SDM, which was urine flow related, was 1/7 of that of creatinine, indicating reabsorption of the parent drug. The unbound N4-SDM was eliminated three times faster than creatinine, indicating that tubular secretion was the predominant mechanism of excretion. After i.v. administration, 51.9% of the administered dose was recovered in urine within 72 h p.i., one quarter of which as SDM and three quarters as N4-SDM. Tissue distribution data obtained at 26, 74, 168, and 218 h after i.m. injection revealed that the highest SDM concentration was found in plasma. The SDM concentration in muscle, liver, and kidney ranged from one third to one fifth of that in plasma. The N4-SDM formed a minor part of the sulphonamide content in edible tissues, in which the SDM as well as the N4-SDM concentration parallelled the plasma concentrations. Negative results obtained with a semi-quantitative bioassay method, based on monitoring of urine or plasma, revealed that the SDM concentration levels in edible tissues were in that case below 0.1 mu/g tissue.     

Pharmacokinetics and renal clearance of sulphadimidine, sulphamerazine and sulphadiazine and their N4-acetyl and hydroxy metabolites in pigs

The effect of molecular structure on the drug disposition and protein binding in plasma, the urinary recovery, and the renal clearance of sulphamerazine (SMR), sulphadiazine (SDZ), and sulphadimidine (SDM) and their N4-acetyl and hydroxy derivatives were studied in pigs. Following IV administration of SDM, SMR and SDZ, their mean elimination half-lives were 12.4 h, 4.3 h and 4.9 h respectively. The plasma concentrations of parent sulphonamide were higher than those of the metabolites, and ran parallel. The acetylated derivatives were the main metabolites; traces of 6-hydroxymethylsulphamerazine and 4-hydroxysulphadiazine were detected in plasma. The urine recovery data showed that in pigs acetylation is the major elimination pathway of SDM, SMR and SDZ; hydroxylation became more important in case of SMR (6-hydroxymethyl and 4-hydroxy derivatives) and SDZ (4-hydroxy derivatives) than in SDM. In pigs methyl substitution of the pyrimidine side chain decreased the renal clearance of the parent drug and made the parent compound less accessible for hydroxylation. Acetylation and hydroxylation speeded up drug elimination, because their renal clearance values were higher than those of the parent drug.     

Isolation and metabolism cage system for newborn pigs.

An isolation system was designed and constructed for isolating normal and infected newborn pigs. The system consisted of an outer cage fitted with a biological diffusion filter and a dunk bath entry system and an inner metabolism cage to contain the pig. When tested with S-13 bacteriophage, the isolation and metabolism cage system was at least 99% efficient in preventing the entry or escape of microorganism. A total of 267 Escherichia coli-infected newborn pigs have been isolated in these units, with no cross contaminations.     

Experimental Aujeszky's disease in pigs: excretion, survival and transmission of the virus

Airborne Aujeszky's disease virus was recovered from looseboxes containing groups of pigs infected with virus strains from England, Northern Ireland and Denmark from days 1 to 7 after infection. Pigs sampled individually excreted most airborne virus on days 2 and 3 after infection. On a 24 hour basis the maximum amount of airborne virus excreted per pig was log10 5.3 TCID50. Subclinical infection was transmitted from a clinically affected group of pigs to a seronegative group held in separate looseboxes when air was drawn through ducting connecting one box with the other. Tissues taken from pigs killed at varying times after infection showed that the main sites of virus replication were in the head and neck region. Aujeszky's disease virus was detected for up to 40 days in a range of tissues taken from pigs at the acute stage of disease and stored at -20 degrees C.     

Pharmacokinetics, metabolism, and renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N4-acetyl and hydroxy metabolites in calves and cows

The effect of molecular structure on the drug disposition and protein binding in plasma and milk, the urinary recovery, and the renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N4-acetyl and hydroxy derivatives were studied in calves and cows. Sulfadiazine was highly acetylated and was slightly hydroxylated. Sulfamerazine and sulfamethazine were hydroxylated predominantly at the methyl group of the pyrimidine side chain; hydroxylation of the pyrimidine ring itself was more extensive for sulfamethazine than for sulfamerazine. At dosages between 100 and 200 mg/kg of body weight, sulfamethazine had a capacity-limited elimination pattern, which was not observed for sulfadiazine or sulfamerazine. The concentrations of the parent sulfonamide and its metabolites in plasma and milk were parallel, the latter being lower. Metabolite concentrations in milk were at least 8 times lower than those of the parent drug. Metabolism speeds drug elimination, producing compounds with renal clearance values higher than those of the parent drug. The effect on the metabolism and renal clearance of methyl substitution in the pyrimidine side chain is discussed.     

肠道微生物-肠-脑轴与猪营养代谢

肠-脑轴是肠道与大脑通过神经和内分泌介导的一种双向应答系统,越来越多的研究表明,肠道菌群在此轴中发挥着关键作用。因此,微生物-肠-脑轴之间的双向交流关系逐渐成为动物营养代谢以至人类健康和疾病中热门的研究方向。肠道微生物群与宿主相互作用,从而控制体内平衡。本文从微生物与宿主肠道以及脑神经系统之间的相互关系入手,综述了微生物-肠-脑轴在猪营养代谢中的研究进展。     

The role of plasma protein binding on the metabolism and renal excretion of sulphadimethoxine and its metabolite N4-acetylsulphadimethoxine in pigs

The effects of plasma protein binding on the elimination of sulphadimethoxine (SDM) were examined after intravenous administration of 6.25, 12.5, 25, 50, 100 and 150 mg/kg to pigs. At an early stage of the experiment, the animals were anaesthetised by inhalation of enflurane to obtain a more exact relationship between plasma concentration and the renal excretion. SDM and its acetylated conjugate, N4-acetylsulphadimethoxine (N4-SDM) were detected in plasma and urine of all animals, and the recovery of the doses was almost complete in two animals with negligible renal excretion of SDM. The percentages of plasma protein binding of SDM and N4-SDM were almost similar, and ranged from 30 to 95%, depending on the plasma concentration. The metabolic clearance of SDM by acetylation increased when the plasma protein binding decreased. These results suggested that the main elimination route of SDM in pigs is acetylation, and that the plasma protein binding can have a large effect on the elimination of SDM in pigs. The effect of plasma protein binding on the renal clearance of SDM was not so evident, because urine pH had a much greater effect on it. The deacetylation of N4-SDM was detected after 25 mg/kg intravenous administration of N4-SDM, which suggests that the metabolic clearance of SDM is part of an acetylation-deacetylation equilibrium. Saturation of the active tubular reabsorption of SDM and of the active tubular secretion of N4-SDM was also suggested after higher doses of SDM.     

Effect of hypophosphatemia on muscle metabolism after exercise in pigs.

Five Swedish Landrace pigs with a mean weight of 51 +/- 5 kg performed an exercise test on a treadmill at a speed of 1.8 m/s and a duration of 10 min. Hypophosphatemia was then induced in these pigs by addition of aluminium hydroxide (liquid antacid) to the normal feed. After 3 weeks, the exercise test was repeated when the mean weight of the pigs was 65 +/- 9 kg. Five other Swedish Landrace pigs with a mean weight of 72 +/- 4 kg performed a similar exercise test. Muscle biopsies from M. biceps and blood samples were taken from all pigs 3-5 days before and immediately after each exercise test. Hypophosphatemic pigs had significantly lower serum phosphate and higher aluminium levels than normophosphatemic pigs. In all pigs, glycogen content in muscle decreased significantly (-108 to -135 mmol/kg muscle) with exercise while no changes were seen in adenosine triphosphate, creatine phosphate or inorganic phosphate concentrations. In normophosphatemic pigs, glucose-6-phosphate and lactate concentrations increased significantly during exercise by 2-4 mmol/kg and 12.8-14.4 mmol/kg, respectively. However, in hypophosphatemic pigs, glucose-6-phosphate concentrations decreased significantly during exercise by 4.4 mmol/kg and lactate levels were unchanged. These results indicate that low serum inorganic phosphate levels influence muscle metabolism and glycolysis in connection with physical exercise.     

Pharmacokinetics, metabolism and excretion of phenylbutazone in cattle following intravenous, intramuscular and oral administration

The absorption, metabolism and urinary excretion of phenylbutazone were investigated in six adult cattle in a cross-over study involving administration intravenously, intramuscularly and orally at a dose rate of 4.4 mg kg-1. Following intravenous injection plasma disposition was described by a three compartment open model with mean elimination half-life (t1/2 beta) and clearance (ClB) values of 35.9 hours and 2.77 ml kg-1 h-1, respectively. Somewhat longer t1/2 beta values were obtained after oral and intramuscular dosing and these may have resulted from sequestration within and slow absorption from the gastrointestinal tract and continual uptake from intramuscular sites following precipitation as a depot. Absorption was more complete after intramuscular than after oral dosing; area under curve values were almost twice as high for the intramuscular route. Double peaks in the plasma concentration time curves after oral dosing were recorded in some cows. These may have resulted from drug adsorption on to and subsequent desorption from hay or as a consequence of enterohepatic shunting. There was no evidence for opening of the oesophageal groove and direct passage of the drug into the abomasum. Two hydroxylated metabolites of phenylbutazone, oxyphenbutazone and gamma-hydroxyphenylbutazone were detected in trace amounts in plasma for 72 hours and in much higher concentrations in urine for 168 hours. Approximate urine:plasma (U/P) concentration ratios for the metabolites approached and occasionally exceeded the U/P ratio for endogenous creatinine, indicating poor reabsorption and, possibly, tubular secretion. Cumulative urinary excretion data indicated that the hydroxylated derivatives of phenylbutazone are probably formed more slowly in cattle than in horses.