Depletion of [14C]-clorsulon in cows' milk

Chiu, Shuet Hing Lee; Baylis, Francis P.; Taub, Rae; Green, Marilyn; Halley, Bruce A.; Bodden, R. M.

doi:10.1021/jf00087a054

Cited by 11 publications

(4 citation statements)

References 6 publications

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“…Lactating dairy cows given a single oral dose of ''C-labelled clorsulon at 7 mg/kg developed peak serum concentrations at post-dosing times ranging from 12-30 h (Chiu et aL, 1989). These values are consistent with the T, , , values of 15 h and 14 h reported for sheep and goats, respectively in the present study.…”

Section: Discussionsupporting

confidence: 90%

Clorsulon pharmacokinetics in sheep and goats following oral and intravenous administration

Sundlof

Whitlock

1992

Vet Pharm & Therapeutics

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Clorsulon was measured in plasma and urine of sheep and goats after administration of a single intravenous (i.v.) and after a single oral dose of 7 mg/kg. A three-compartment model with elimination occurring from the central compartment was determined to best describe the i.v. data, whereas a one-compartment model with a single exponential absorption phase best described the oral plasma data. The bioavailability of orally administered clorsulon was approximately 55% in goats and 60% in sheep. Peak plasma concentrations occurred at 14 h and 15 h after oral administration in goats and sheep, respectively. Absorption from the gastro-intestinal tract effectively prolonged the elimination of clorsulon by increasing the elimination half-life from 17 to 28 h in sheep and from 12 to 23 h in goats for the i.v. and oral routes, respectively. In both goats and sheep, approximately 50% of the i.v. dose was recovered in urine as parent drug at 48 h after administration, whereas 41% and 30% of the dose was recovered after oral administration for goats and sheep, respectively. The elimination rate constant (kel) in goats was nearly twice as large as the value determined in sheep, and the urea under the i.v. plasma curve in goats was only 63% of the value in sheep indicating that goats are more effective in their capacity to eliminate clorsulon than are sheep. These differences in drug disposition between sheep and goats may account for the reduced efficacy of clorsulon reported in goats.

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Section: Discussionsupporting

confidence: 90%

Clorsulon pharmacokinetics in sheep and goats following oral and intravenous administration

Sundlof

Whitlock

1992

Vet Pharm & Therapeutics

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“…The relative contribution of biliary excretion is unknown, although the presence of the drug in liver tissue is said to be ''a reflection of liver function in excretion of the sulphonamide'' (Schulman et al 1979). Indeed, little is known about the metabolism of clorsulon, either, but biotransformation of clorsulon is considered to play only a minor role in its elimination (Chiu et al 1989;Sundlof and Whitlock 1992). Consequently, the data available suggest that oral entry is more important than transtegumental diffusion for the uptake of clorsulon, with the expectation that the gut may be more severely affected than the tegument.…”

Section: Introductionmentioning

confidence: 99%

Transmission electron microscope study of the ultrastructural changes induced in the tegument and gut of Fasciola hepatica following in vivo drug treatment with clorsulon

Meaney¹,

Fairweather

Brennan

et al. 2004

Parasitology Research

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Using transmission electron microscopy (TEM), both the tegument and gut of Fasciola hepatica were examined in an effort to identify and characterise the ultrastructural changes induced following treatment with the flukicidal drug clorsulon. Male Sprague-Dawley rats infected with F. hepatica were dosed orally at 8-8.5 weeks post-infection with clorsulon at a concentration of 12.5 mg/kg body weight. After 24, 48 and 72 h, rats were sacrificed by cervical dislocation and mature flukes recovered from the bile ducts. After 24 h treatment in vivo, disruption of the tegumental syncytium was concentrated at the apex of the syncytium where a dark band consisting of numerous secretory bodies was present. Some blebbing of the apex had also occurred, "open" bodies were present in this region and the mitochondria were slightly swollen. In the cell bodies, swelling of the mitochondria and their cristae had also occurred and the Golgi complexes appeared to be smaller than normal. The disruption seen after 48 h treatment in vivo was similar but more severe: the frequency of blebbing had increased, as had the number of "open" bodies and the swelling of the mitochondria. Vacuoles had begun to appear in the syncytium-both autophagic and electron-lucent-and swelling of the mucopolysaccharide masses around the basal infolds had occurred. Lipid droplets were observed occasionally. In the cell bodies, autophagic vacuoles had begun to appear and swelling of the mitochondria had increased in severity. After 72 h treatment in vivo, more severe disruption was seen in the tegumental syncytium in which widespread swelling and blebbing of the apex was apparent. The basal infolds had become very badly swollen in a number of specimens and damage to the spines was evident. The mitochondria remained swollen, as did the mucopolysaccharide masses around the basal infolds. Lipid droplets were more frequently observed in the syncytium. In the tegumental cells, swelling of the mitochondria was greater and an increase in the number of autophagic vacuoles was apparent. The gut showed signs of disruption after 24 h treatment in vivo, in that the surface lamellae were disrupted and a build-up of autophagic vacuoles at the apex of the cells had taken place. Swelling of the mitochondria and the cisternae of granular endoplasmic reticulum (gER) was evident. There was a decrease in the number of secretory bodies. After 48 h treatment in vivo, the number of autophagic vacuoles in the gastrodermal cells had increased, the mitochondria and gER remained swollen and the disruption seen to the lamellae was still evident. In the 72 h-treated specimens, the disruption seen in the gastrodermal cells had increased significantly, with severe vacuolation of the apical cytoplasm. An increase in the number of autophagic vacuoles was evident, the mitochondria and the gER remained swollen and lipid droplets were present in the cells.

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“…The pharmacokinetics of clorsulon were characterized by the determination of the plasma concentrations of the unchanged molecule because studies in rats and cattle indicated that clorsulon is only minimally metabolized following administration (Chiu et al, 1985(Chiu et al, , 1989Schulman et al, 1979) suggesting that the parent molecule is the appropriate marker substance. In addition, in vitro studies have shown that oral ingestion of unchanged clorsulon by the liver fluke is responsible for its fasciolicidal activity (Meaney et al, 2005a(Meaney et al, , 2005b.…”

Section: Discussionmentioning

confidence: 99%

Plasma pharmacokinetics of clorsulon following administration of a single subcutaneous or intravenous injection to cattle

Rehbein,

Kvaternick,

Kellermann

et al. 2023

Vet Pharm & Therapeutics

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The benzenedisulfonamide derivative clorsulon is a potent fasciolicide which is marketed in fixed combination injectables, typically combined with the macrocyclic lactone ivermectin. In the presented pharmacokinetic study, the plasma profile of clorsulon in 32 healthy, young Brown Swiss cattle was administered a single intravenous dose at 3 mg/kg body weight or subcutaneously at 3, 6 or 12 mg/kg body weight (4 intact male and 4 female animals per treatment) as a 30% w/v clorsulon injection formulation. Serial blood samples were collected up to 24 days after administration to establish the pharmacokinetics, bioavailability and dose proportionality of clorsulon. Following a single intravenous injection of clorsulon at 3 mg/kg body weight, the area under the concentration versus time curve from the start of dose administration to the time of the last quantifiable concentration (AUClast) was 4830 ± 941 day*ng/mL, and half‐live was 2.37 ± 0.98 days. The back extrapolated concentration at time 0 was 38,500 ± 6070 ng/mL. The volume of distribution at steady state and clearance were 685 ± 107 mL/kg and 664 ± 127 mL/day/kg, respectively. In the groups dosed at 3, 6 or 12 mg/kg body weight by subcutaneous injection, clorsulon plasma concentrations rose to maximum within 0.5 day and decreased to the last sample point. For these groups, the maximum plasma clorsulon concentrations were 3100 ± 838, 5250 ± 1220 and 10,800 ± 1730 ng/mL, respectively, and the AUClast was 5330 ± 925, 9630 ± 1300 and 21,500 ± 3320 day*ng/mL, respectively. Half‐lives, 2.01 ± 0.62, 3.84 ± 1.42 and 5.36 ± 0.60 days, respectively, increased significantly with dose, likely related to increasing dose volume. Clorsulon was well absorbed and fully bioavailable (103%–114%) after subcutaneous injection. No gender‐related difference in systemic exposure was observed. Assessment of Cmax and AUClast demonstrated a proportional increase in systemic exposure to the clorsulon subcutaneous doses over the range of 3–12 mg/kg body weight.

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Depletion of [14C]-clorsulon in cows' milk

Cited by 11 publications

References 6 publications

Clorsulon pharmacokinetics in sheep and goats following oral and intravenous administration

Clorsulon pharmacokinetics in sheep and goats following oral and intravenous administration

Transmission electron microscope study of the ultrastructural changes induced in the tegument and gut of Fasciola hepatica following in vivo drug treatment with clorsulon

Plasma pharmacokinetics of clorsulon following administration of a single subcutaneous or intravenous injection to cattle

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