Triclopyr

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Katherine Z Isoardi - One of the best experts on this subject based on the ideXlab platform.

Colin B Page - One of the best experts on this subject based on the ideXlab platform.

C Timchalk - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics of Triclopyr 3 5 6 trichloro 2 pyridinyloxyacetic acid in the beagle dog and rhesus monkey perspective on the reduced capacity of dogs to excrete this organic acid relative to the rat monkey and human
    Toxicology and Applied Pharmacology, 1997
    Co-Authors: C Timchalk, R J Nolan
    Abstract:

    The pharmacokinetics of Triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) were measured in the beagle dog and rhesus monkey and compared with the kinetics observed in rats and humans. In addition, studies were conducted in anesthetized dogs to better understand the mechanism by which [14C]Triclopyr is eliminated in this species. Triclopyr was dissolved in distilled water, and administered as a single oral dose of 0.5, 5, or 20 mg/kg to three male dogs. A single male rhesus monkey was given an intravenous dose of 30 mg [14C]Triclopyr/kg body wt on two occasions separated by 10 days. Anesthetized male dogs, were implanted with venous, arterial, and urethral catheters and given increasing amounts of Triclopyr to produce plasma Triclopyr levels ranging from 0.3 to 27 microg eq/mL. In the monkey, Triclopyr was rapidly eliminated from the plasma (t1/2 = 6.3 hr) with >95% of the urinary 14C activity excreted within 24 hr postdosing. In the dog, orally administered Triclopyr was rapidly and effectively absorbed at every dose level with virtually all of it excreted in the urine by 72 hr postdosing. However, the kinetics were slightly nonlinear, and the fraction of the dose excreted in the urine decreased with increasing dose. Several nonlinear processes may collectively contribute to the modest nonlinear pharmacokinetics in the dog. Plasma protein binding of Triclopyr in the dog ranged from 94 to 99%, was nonlinear, and was an important determinant in the renal clearance of Triclopyr. The nonlinear plasma protein binding indicates that glomerular filtration became disproportionately more important as plasma Triclopyr concentration increased. There was good evidence for a high-affinity low-capacity active-secretory process that was saturated by low plasma Triclopyr concentrations. As plasma Triclopyr concentrations increased, tubular reabsorption begins to exceed secretion, resulting in decreased renal clearance. The volume of distribution, normalized for body weight, was constant across all species. While clearance and half-life could be allometrically scaled to body weight for the rat, monkey, and human, the dog had a much slower clearance and longer half-life for Triclopyr elimination than predicted allometrically. These data demonstrate that the pharmacokinetics of Triclopyr in the dog are markedly different than in rat, monkey, and human.

  • evaluation of renal function in rhesus monkeys and comparison to beagle dogs following oral administration of the organic acid Triclopyr 3 5 6 trichloro 2 pyridinyloxyacetic acid
    Toxicological Sciences, 1997
    Co-Authors: C Timchalk, D R Finco, J F Quast
    Abstract:

    Abstract The current study evaluated the effects of Triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) on renal function following oral administration in the beagle dog and rhesus monkey. Male rhesus monkeys were orally administered Triclopyr by gavage at a dose of 5 mg/kg/day, 7 days/week for 28 days, after which the dosage was increased to 20 mg/kg/day for 102 consecutive days. Groups of male dogs were administered either a single oral dose of 5 mg/kg Triclopyr or were fed a diet spiked with Triclopyr at a dose of 5 mg/kg/day for 47 consecutive days. The following functional and clinical chemistry parameters were evaluated: exogenous phenolsulfonphthalein (PSP) excretion, inulin andpara-aminohippurate (PAH) clearance (monkeys only), endogenous serum creatinine, and blood urea nitrogen (BUN) at multiple time points during the study. Creatinine, BUN, and inulin clearance were within the normal range from both species following Triclopyr administration which indicates that repeated administration of Triclopyr in the dog and monkey had no effect on glomerular filtration rate (GFR). In monkeys, the percentage excretion of PSP and PAH appeared to increase following Triclopyr administration (20 mg/kg/day), suggesting that these weak organic acids may be competing for the same plasma protein-binding site enhancing their clearance. More importantly, these data strongly suggest that Triclopyr is not competing with PSP or PAH for the active secretory site within the monkey kidney proximal tubules. In contrast, PSP clearance studies in dogs clearly demonstrated that Triclopyr administration (5 mg/kg) can significantly decrease the percentage PSP excretion even following a single dose administration. The decrease in percentage PSP was reversible and inversely related to the plasma Triclopyr concentration. Overall, these data clearly indicate that Triclopyr effectively competes with PSP for the active secretory site within the dog kidney proximal tubules. In contrast, the monkey was insensitive to the effects of Triclopyr on the active secretory process even at doses fourfold higher (20 mg/kg/day) than the effective dose in the dog (5 mg/kg/day). These findings suggest that the effect observed on PSP and PAH excretion in the dog represent a physiological competition for excretion and not toxicity.

Geoffrey K Isbister - One of the best experts on this subject based on the ideXlab platform.

Michael S Roberts - One of the best experts on this subject based on the ideXlab platform.

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