The fate of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) following oral administration to man

Five human male volunteers ingested a single dose of 5 mg/kg without incurring detectable clinical effects. Concentrations of 2,4,5-T in plasma and its excretion were measured at intervals after ingestion. The clearances of 2,4,5-T from the plasma as well as its excretion from the body occurred via apparent first-order rate processes with half-lives of 23.10 and 23.06 hr, respectively. Essentially all of the 2,4,5-T was absorbed into the body and excreted unchanged in the urine. In the body, 65% of the 2,4,5-T resided in the plasma where 98.7% was bound reversibly to protein. The volume of distribution was 0.079 liters/kg. Utilizing the kinetic constants from the single dose experiment, the expected concentrations of 2,4,5-T in the plasma of individuals receiving repeated daily doses of 2,4,5-T were calculated. From these calculations, it was determined that the plasma concentrations would essentially reach a plateau after 3 days. If the daily dose ingested in mg/kg is A₀, the concentration in the plasma after attaining plateau would range from 12.7 A₀ to 22.5 A₀ μg/ml. This range would converge to approximately 17 A₀ μg/ml as the daily dose A₀ is distributed throughout the day.     

Cytoskeletal perturbation induced by herbicides, 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T)

To understand the mechanisms of toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), we have studied their effects on the cytoskeletal organization, particularly microtubules (MT) and microfilaments (MF), DNA synthesis, and the synthesis and composition of cytoskeletal proteins in mouse 3T3 cells. Exposure of cells to 2,4-D or 2,4,5-T resulted in a dose-dependent inhibition of DNA synthesis; 50% inhibition occurred at 2.21 mM and 0.90 mM for 2,4-D and 2,4,5-T, respectively. Furthermore, a strong synergistic inhibition of DNA synthesis was produced by mixtures (each having a total concentration of 1.25 mM) of 2,4-D with 2,4,5-T. Similarly, 2,4,5-T is more potent than 2,4-D in causing cytoskeletal perturbation as revealed by fluorescence microscopy. Treatment of cells with 2,4-D (2.5 mM) or 2,4,5-T (1.25 mM) for 20 h resulted in severe MT aggregation and the appearance of large bundles, which were organized in a rope-like structure in the former and a dramatic octopus-like pattern in the latter. Further, MT bundling is particularly severe in the cell center. Under these conditions, marked changes in MF organization also occurred as evidenced by clustering and crisscrossing of MF in the perinuclear region. A 1:1 mixture (final = 1.25 mM) of 2,4-D and 2,4,5-T, a formulation equivalent to Agent Orange composition, also induced a dramatic perturbation to the organization of MT and MF, resulting in the formation of ring-like structures. MT bundling is still apparent, especially around the outer edge of the "rings." MF are localized predominantly along the cell periphery, where they appear to be aggregated tightly forming patches. Surprisingly, the synthesis and composition of cytoskeletal proteins, which are resistant to detergent extraction but released by CaCl2, are essentially unaffected by 2,4-D or 2,4,5-T. These results suggest that the dramatic perturbation of the cytoskeletal morphology caused by these herbicides probably only results from a structural reorganization and redistribution of MT and MF.     

In vitro uptake of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) by renal cortical tissue of rabbits and rats

The active transport of 2,4-D and 2,4,5-T by renal cortical slices of rats and rabbits has been characterized with in vitro techniques. Renal cortical slices, prepared from both species, accumulate 2,4-D and 2,4,5-T, although greater uptake, was noted with rabbit tissue. Nitrogen and various metabolic inhibitors reduced the uptakes. This indicates that these processes are energy dependent. The enhancement of accumulation by the addition of certain metabolic substrates, e.g. acetate, lactate, provides evidence that both organic acid herbicides are transported by the renal organic anion mechanism. Potassium-ion stimulation also supports this concept. It is concluded that the renal tubular transport by the organic anion mechanism may account for the relatively rapid disappearance of these compounds, which in turn may contribute to their low toxicity.     

The fate of 2,4-dichlorophenoxyacetic acid (2,4-D) following oral administration to man

The pharmacokinetic profile of 2,4-D is defined in man. Five male human volunteers ingested a single dose of 5 mg/kg 2,4-D without detectable clinical effects. Concentration of 2,4-D were determined in plasma in 3 of 5 subjects and in urine in all subjects at intervals after ingestion. The elimination of 2,4-D from plasma in all subjects occurred by an apparent first-order rate process with an average half-life ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$) of 11.6 h. All subjects excreted 2,4-D in the urine with an average $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ of 17.7 h. Excretion occurred mainly as 2,4-D (82.3%) with smaller amounts excreted as a 2,4-D conjugate (12.8%). Essentially all of the 2,4-D was absorbed from the gastrointestinal tract in man. Clearance of 2,4-D from the plasma and excretion from the body are first-order rate processes. There was no evidence that 2,4-D would accumulate following repeated administration.     

The metabolism and distribution of 2,4,5-trichlorophenoxyacetic acid in female rats

[1-¹⁴C]-2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) was fed to pregnant and non-pregnant female rats at various dosages, and expired air, urine, feces, internal organs and tissues were analyzed for radioactivity. During the first 24 hr, 75 ± 7% of the radioactivity was excreted in the urine and 8.2 ± 4.6% in the feces. No ¹⁴C was found in the expired air. There was no significant difference in the rate of elimination between the pregnant and nonpregnant rats, or among the dosages used. Radioactivity was detected in all tissues, with the highest concentration being found in the kidney. The maximum concentration of radioactivity in all tissues was generally reached between 6 to 12 hr after po dosing and then started to decline rapidly. Radioactivity was also detected in the fetuses and in the milk. The average biological half-life of 2,4,5-T in the organs was 3.4 hr for the adult rats and 97 hr for the newborn.     

Interspecies differences on pharmacokinetics of rebamipide following oral administration to rats and dogs

Rebamipide is used widely in East Asia for the treatment of gastric ulcers, acute gastritis, and exacerbated chronic gastritis. The objective of this study was to investigate the pharmacokinetic (PK) properties of rebamipide following single oral administration in rats and dogs. Eleven rats and dogs received single oral administrations of rebamipide (35 mg/kg and 100 mg, respectively). Blood samples were collected according to the assigned schedule, and the plasma concentration of rebamipide was determined using liquid chromatography–tandem mass spectrometry. A double-peak phenomenon was observed in the PK profile of rebamipide in rats. In contrast, rebamipide showed a conventional PK profile without double peaks in dogs. The half-life of rebamipide in rats (12.85 ± 7.86 h) was longer than that in dogs (5.62 ± 2.24 h), and the apparent total clearance (Cl_t/F) of rebamipide in rats (3.32 ± 1.18 L/h) was lower than that in dogs (105.01 ± 42.37 L/h). Simple allometric approaches showed that the correlation between body weight and Cl_t/F (R² = 0.9287) among rats, dogs, and humans appeared satisfactory. This finding will help not only in understanding the pharmacology of rebamipide but also in establishing a strategy for in vivo evaluation of novel rebamipide formulations.     

Distribution of 2,4,5-trichlorophenoxyacetic acid in the mouse fetus

The herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) readily crosses the placenta in the mouse on gestational day 13. Concentrations of 2,4,5-T in maternal tissues and fetuses were obvious at 30 min, highest at 8 h, diminished by 24 h and almost entirely eliminated by 48 h. Autoradiographs of the whole fetus showed that initially 2,4,5-T was mainly in the highly vascularized tissues such as liver followed by the skin, eyes and ventricles of the brain. At 48 h, there was a general distribution of 2,4,5-T in the skeletal muscles. None was detected in the palate. The excretion rate in the mouse was approx. 60 gm/h; about 52% of the dose was recovered unchanged in the urine in 24 h.     

The fate of N-nitrosodiethanolamine after oral and topical administration to rats

¹⁴C-labelled N-nitrosodiethanolamine ([¹⁴C]NDELA) was given to Osborne-Mendel rats at two dose levels, 0·5 or 50 mg/kg, by oral or topical administration. The excreta and tissues were analysed at various times from 4 hr to 1 wk after administration to determine the distribution of radioactivity. After oral administration, [¹⁴C]NDELA was rapidly absorbed from the gastro-intestinal tract, distributed throughout all organs and tissues, and then excreted, mainly via the kidneys. The tissue concentration reached a peak at 8 hr, but some activity remained after 1 wk. After topical application NDELA was slowly absorbed percutaneously, but once absorbed was distributed as in the orally dosed rats. Metabolic profiles of urine and bile samples from both the orally and topically dosed rats were identical, although the quantities varied. In addition to unchanged NDELA, one metabolite was present. The dose level had little effect on the quantities of unchanged NDELA or the metabolite present.     

比格犬口服西格列羧的毒代动力学

目的研究治疗糖尿病新药西格列羧长期毒性剂量下,原形药物在比格犬体内的毒代动力学,以评价西格列羧的全身暴露水平,确定暴露水平与给药剂量和性别的相互关系。方法采用高效液相色谱-紫外检测的方法分析比格犬血浆中的药物浓度。结果比格犬每天给药1次(6,18和54 mg.kg-1)连续14 d,d 1给药后雌性比格犬的平均AUC(0-T)值为3.4,8.4和33.0 mg.h.L-1,雄性比格犬的平均AUC(0-T)值为4.2,5.9和32.3 mg.h.L-1,d 14给药后雌性比格犬的平均AUC(0-T)值为2.5,13.9和16.0 mg.h.L-1,雄性比格犬的平均AUC(0-T)值为2.0,18.6和15.5 mg.h.L-1,对所有的剂量水平和两种性别平均AUC(0-T)值大部分与剂量相关。平均cmax值大部分也与剂量相关增高,第1次给药后雌性比格犬的平均cmax值为0.45,1.59和4.93 mg.L-1,雄性比格犬的平均cmax值为0.94,1.43和8.69mg.L-1,d 14给药后雌性比格犬的平均cmax值为0.40,2.97和3.49 mg.L-1,雄性比格犬的平均cmax值为0.39,4.16和4.01 mg.L-1。平均tmax值为2~8 h,表明吸收比较缓慢。消除半衰期t1/2在1.6~5.7 h之间,大部分为2~3 h。结论西格列羧原形药物的全身暴露水平与给药剂量的相关性为:单次给药后正相关,连续14 d给药后中高剂量组的相关性不明显。     

Some pharmacokinetic parameters of salvianolic acid A following single-dose oral administration to rats

Context: Salvianolic acid A (Sal A) is a hydrophilic bioactive compound isolated from Salvia miltiorrhiza Bunge (Lamiaceae). It exerts beneficial effects after oral administration on diabetic complications.

Objective: To systematically study the absorption, distribution and excretion of Sal A after single-dose oral administration.

Materials and methods: Animal experiments were conducted in Sprague-Dawley rats. Plasma was sampled at designated times after oral doses of 5, 10 and 20?mg/kg, and an intravenous dose of 50?μg/kg. Tissues were harvested at 10, 60 and 120?min postdosing. Bile, urine and feces were collected at specified intervals before and after dosing. Absorption and distribution characteristics were analyzed by LC–MS, and excretion characteristics were analyzed by UPLC–MS/MS. The Caco-2 cell model was applied to investigate potential mechanisms.

Results: The C_max (5?mg/kg: 31.53?μg/L; 10?mg/kg: 57.39?μg/L; 20?mg/kg: 111.91?μg/L) of Sal A increased linearly with doses (r> 0.99). The calculated absolute bioavailability was 0.39–0.52%. Transport experiment showed poor permeability and the ratio of P_B–A to P_A–B was 3.13–3.97. The highest concentration of Sal A was achieved in stomach followed by small intestine and liver, and it could also be detected in brain homogenate. Approximately 0.775% of its administered dose was excreted via feces, followed by bile (0.00373%) and urine (0.00252%).

Discussion and conclusions: These results support the future development of Sal A as an oral drug for the treatment of diabetic complications. Future research should be conducted to investigate the reason for its poor bioavailability and improve this situation.     

Neurotoxicity and toxicokinetics of artelinic acid following repeated oral administration in rats

Neurotoxicity secondary to oil-soluble artemisinins has been reported in various animal species. The onset of neurotoxicity and toxicokinetics of oral artelinic acid (AL), a water-soluble artemisinin, were investigated. After dose range study, rats were dosed at either 160 mg/kg daily for 9 consecutive days or at 288 mg/kg once every other day for five doses, so that the total dose (1440 mg/kg) and duration (9 days) were identical. Neuronal damage of varying severity was identified beginning as early as 1 day after completing dosing and continued for up to 10 days post dosing. Neuronal injury was most severe 7 days after the last treatment in each of the two dosing regimens. The rats dosed with 160 mg/kg of AL daily showed moderate neurotoxicity and lost 22% of their body weight during treatment. Compared with the first dose, the toxicokinetic profile of this regimen changed significantly, with the elimination half-life increasing 3.82-fold and the volume of distribution increasing 5.23-fold on the last day of dosing. In the animals treated with AL at 288 mg/kg every other day for 5 doses, minimal neuronal degeneration (severity score 1.17) was identified and the body weight was only 8% loss. Furthermore, there were no obvious differences in the pharmacokinetic parameters between first and last dosing days with this regimen. Additionally, a progressively drug retention in stomach and drug accretion in blood were only found in rats treated with 160 mg/kg daily for 9 days. These results imply that delayed gastric emptying resulted in AL accumulation in blood and prolonged a neurotoxic exposure time (186 h) in 160 mg/kg rats when compared to that (75 h) in 288 mg/kg animals. Therefore, the drug exposure time is a key factor in the neurotoxicity induced by AL.     

Effects of 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid on peroxisomal enzymes in rat liver

The effects of feeding 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) on the level of peroxisomal enzymes in rat liver were studied. The concentration of triglyceride in serum was decreased and the activity of cyanide-insensitive palmitoyl-CoA oxidation, catalase and carnitine acetyltransferase increased. However, the extent of the increase in the activity of these enzymes by treatment with 2,4-D was less pronounced than that by 2,4,5-T treatment. The administration of 2,4-D or 2,4,5-T increased the concentration of polypeptide with a mol. wt of 80,000 in the light mitochondrial fractions of the liver from the rats.     

Inhibition of human glutathione S-transferases by 2,4-dichlorophenoxyacetate (2,4-D) and 2,4,5-trichlorophenoxyacetate (2,4,5-T)

The phenoxyacid herbicides, 2,4-dichlorophenoxyacetate (2,4-D) and 2,4,5-trichlorophenoxyacetate (2,4,5-T), inhibit all known isoenzymes of human liver and erythrocyte glutathione (GSH) S-transferase. However, the maximal inhibition and the I50 values vary significantly for different isoenzymes. GSH peroxidase II activity of GSH S-transferases is also inhibited by both these compounds. These studies suggest that the effect of these compounds on human GSH S-transferases is significantly different from that reported for rat liver enzymes.     

Specific teratogenic action of 2,4,5-trichlorophenoxyacetic acid on mouse and rat whole-embryo cultures

The effects of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) were studied at concentrations ranging from 0.17 to 3.52 m on post-implanted mouse and rat embryos cultured for 48 hr, either in the absence of any metabolic activation system or in the presence of mouse and rat S-9 mix. 2,4,5-T proved to be a potential teratogen, at 0.88 and 1.76 m , on mouse embryos in the absence of any metabolic activation system. In the presence of mouse S-9 mix, 2,4,5-T showed a high teratogenic potential at 0.17, 0.88 and 1.76 m . In contrast, in the presence of rat S-9 mix, 2,4,5-T induced structural defects only at 1.76 m . At 3.52 m , 2,4,5-T was 100% embryolethal with or without S-9 mix. On rat embryos, 2,4,5-T was potentially teratogenic only in the presence of mouse S-9 mix, causing a significant increase in dysmorphogenic effects at 0.17, 0.88 and 1.76 m . With or without rat S-9 mix, 2,4,5,-T was only embryolethal to rat embryos at 1.76 and 3.52 m . The abnormalities mainly involved the forebrain, the midbrain and the branchial arches. These results are consistent with the known in vivo embryotoxic action of this compound.     

The biological fate of decabromodiphenyl ethane following oral,dermal or intravenous administration

1.?It was important to investigate the disposition of decabromodiphenyl ethane (DBDPE) based on concerns over its structural similarities to decabromodiphenyl ether (decaBDE), high potential for environmental persistence and bioaccumulation, and high production volume.

2.?In the present study, female Sprague Dawley rats were administered a single dose of [¹⁴C]-DBDPE by oral, topical or IV routes. Another set of rats were administered 10 daily oral doses of [¹⁴C]-DBDPE. Male B6C3F1/Tac mice were administered a single oral dose.

3.?DBDPE was poorly absorbed following oral dosing, with 95% of administered [¹⁴C]-radioactivity recovered in the feces unchanged, 1% recovered in the urine and less than 3% in the tissues at 72?h. DBDPE excretion was similar in male mice and female rats. Accumulation of [¹⁴C]-DBDPE was observed in liver and the adrenal gland after 10 daily oral doses to rats.

4.?Rat and human skin were used to assess potential dermal uptake of DBDPE. The dermis was a depot for dermally applied DBDPE; conservative estimates predict ～14?±?8% of DBDPE may be absorbed into human skin in vivo; ～7?±?4% of the parent chemical is expected to reach systemic circulation following continuous exposure (24?h).

5.?Following intravenous administration, ～70% of the dose remained in tissues after 72?h, with the highest concentrations found in lung (1223?±?723?pmol-eq/g), spleen (1096?±?369?pmol-eq/g) and liver (366?±?98?pmol-eq/g); 5?±?1% of the dose was recovered in urine and 26?±?4% in the feces.