scholarly journals Ocular Distribution and Pharmacokinetics of Lifitegrast in Pigmented Rabbits and Mass Balance in Beagle Dogs

2018 ◽  
Vol 34 (1-2) ◽  
pp. 224-232 ◽  
Author(s):  
Jou-Ku Chung ◽  
Elizabeth Spencer ◽  
Matthew Hunt ◽  
Thomas McCauley ◽  
Devin Welty
Keyword(s):  
Mass Balance ◽  
Beagle Dogs ◽  
Pigmented Rabbits ◽  
Ocular Distribution

Unequal Absorption of Radiolabeled and Nonradiolabeled Drug from the Oral Dose Leads to Incorrect Estimates of Drug Absorption and Circulating Metabolites in a Mass Balance Study

2019 ◽  
Vol 13 (1) ◽  
pp. 37-44
Author(s):  
Ryan H. Takahashi ◽  
Jae H. Chang ◽  
Jodie Pang ◽  
Xiaorong Liang ◽  
Shuguang Ma
Keyword(s):  
Oral Dose ◽  
Mass Balance ◽  
Specific Activity ◽  
The Body ◽  
Total Drug ◽  
Beagle Dogs ◽  
Balance Study ◽  
Drug Concentrations ◽  
Specific Activities ◽  
Mass Balance Study

Background: Mass balance studies conducted using radiolabeled material (14C or 3H) definitively characterize the Absorption, Metabolism, and Excretion (AME) of a drug. A critical aspect of these studies is that the radiotracer maintains its proportion to total drug from its administration to its complete elimination from the body. In the study of GDC-0276 in beagle dogs, we observed that the 14C radiotracer proportion (specific activity) varied through the study. Method: High resolution-accurate mass spectrometric measurements of 12C and 14C isotopes of GDC- 0276 and its metabolites in plasma and excreta samples were used to determine the apparent specific activities, which were higher than the specific activity of the dosing formulation. Drug concentrations were adjusted to the observed specific activities to correct the readouts for GDC-0276 AME and PK. Results: The enrichment of 14C, which resulted in higher specific activities, was consistent with faster and more extensive absorption of the radiotracer from the dosing formulation. This resulted in overestimating the dose absorbed, the extent of elimination in urine and bile, and the exposures to circulating metabolites. These biases were corrected by the specific activities determined for study samples by mass spectrometry. Conclusion: Assuming that the radiotracer was proportional to total drug throughout a radiolabeled study was not valid in a 14C study in beagle dogs. This presumably resulted from unequal absorption of the radiotracer and nonradiolabeled test articles from the oral dose due to inequivalent solid forms. We were able to provide a more accurate description of the AME of GDC-0276 in dogs by characterizing the differential absorption of the radiotracer.

Ocular distribution and pharmacokinetics of 125I-OPT302 and 125I-Aflibercept (EYLEA) following intravitreal administration to pigmented rabbits

2014 ◽  
Vol 92 ◽  
pp. 0-0 ◽  
Author(s):  
C STRUBLE ◽  
A TESTER ◽  
M GEROMETTA ◽  
M KREUGER ◽  
J PRUSAKIEWICZ ◽  
...  
Keyword(s):  
Pigmented Rabbits ◽  
Ocular Distribution

The Ocular Distribution of Bunolol in the Eyes of Albino and Pigmented Rabbits

1988 ◽  
Vol 4 (1) ◽  
pp. 37-42 ◽  
Author(s):  
CHI-CHU CHEN ◽  
ROBERT T. KODA ◽  
MARTHA SHACKLETON
Keyword(s):  
Pigmented Rabbits ◽  
Ocular Distribution

OCULAR DISTRIBUTION OF TOPICALLY APPLIED ADRENALINE IN ALBINO AND PIGMENTED RABBITS

2009 ◽  
Vol 62 (5) ◽  
pp. 753-762 ◽  
Author(s):  
ARTO URTTI ◽  
LOTTA SALMINEN ◽  
LASSI PERIVIITA
Keyword(s):  
Pigmented Rabbits ◽  
Ocular Distribution

Ocular distribution of carteolol after single and repeated ocular instillation in pigmented rabbits

2009 ◽  
Vol 72 (6) ◽  
pp. 688-693 ◽  
Author(s):  
Naoki Fujio ◽  
Naotoshi Kusumoto ◽  
Masaaki Odomi
Keyword(s):  
Pigmented Rabbits ◽  
Ocular Distribution

The Clinical, Roentgenological and Morphological Effects of an Acute Exposure of Phosgene on the Lungs of Dogs

1971 ◽  
Vol 29 ◽  
pp. 236-237
Author(s):  
R. F. Bils ◽  
W. F. Diller ◽  
F. Huth
Keyword(s):  
Latent Period ◽  
Chemical Industry ◽  
Toxic Substance ◽  
Lung Edema ◽  
X Rays ◽  
Beagle Dogs ◽  
Male And Female ◽  
Morphological Alterations ◽  
Before And After ◽  
Electron Microscopes

Phosgene still plays an important role as a toxic substance in the chemical industry. Thiess (1968) recently reported observations on numerous cases of phosgene poisoning. A serious difficulty in the clinical handling of phosgene poisoning cases is a relatively long latent period, up to 12 hours, with no obvious signs of severity. At about 12 hours heavy lung edema appears suddenly, however changes can be seen in routine X-rays taken after only a few hours' exposure (Diller et al., 1969). This study was undertaken to correlate these early changes seen by the roengenologist with morphological alterations in the lungs seen in the'light and electron microscopes.Forty-two adult male and female Beagle dogs were selected for these exposure experiments. Treated animals were exposed to 94.5-107-5 ppm phosgene for 10 min. in a 15 m3 chamber. Roentgenograms were made of the thorax of each animal before and after exposure, up to 24 hrs.

Intraneuronal accumulations of lysosomes in the cerebellum of rats and dogs after dosing with MDL-832

1990 ◽  
Vol 48 (3) ◽  
pp. 830-831
Author(s):  
S.D. Barnard ◽  
S.D. Warner
Keyword(s):  
Brown Pigment ◽  
Beagle Dogs ◽  
Sprague Dawley ◽  
Gelatin Capsules ◽  
Pigment Granules ◽  
Sprague Dawley Rats ◽  
Hematoxylin And Eosin ◽  
Dose Levels

1, 2, 9, 10-tetramethoxyaporphine phosphate (MDL-832) was once considered a potential human antitussive. MDL-832 was administered orally in the diets of Sprague-Dawley rats at dose levels of 0, 5, 10, 20, 40, 80 and 160 mg/kg/day for 3 and 6 months and in gelatin capsules to Beagle dogs at 0, 5, 10, 15, 30 and 60 mg/kg/day for 3, 6 and 12 months. Histopathologic examinations of hematoxylin and eosin-stained cerebellar sections revealed intracytoplasmic brown pigment accumulations in large fusiform neurons (presumably the motor type) of the pons. The pigment granules were found to be PAS-positive, non-acid fast, iron-free, Sudan B-positive and fuchsinophilic. Intraneuronal pigment accumulations were seen in rats after 3 months of treatment at 80 mg but not at 40 mg and after 6 months at 20 mg but not at 10 mg. For dogs the effect was observed after 3 months at 60 mg but not at 30 mg and after 12 months at 10 mg but not at 5 mg.

Ultrastructural investigations of MDL 19,660-induced effects on the canine platelet and megakaryocyte

1990 ◽  
Vol 48 (3) ◽  
pp. 374-375
Author(s):  
D.E. Loudy ◽  
J. Sprinkle-Cavallo ◽  
J.T. Yarrington ◽  
F.Y. Thompson ◽  
J.P. Gibson
Keyword(s):  
Antidepressant Drug ◽  
Beagle Dogs ◽  
Long Term Effects ◽  
Short Term ◽  
Platelet Counts ◽  
Toxicological Studies ◽  
Induced Aggregation ◽  
Internal Architecture

Previous short term toxicological studies of one to two weeks duration have demonstrated that MDL 19,660 (5-(4-chlorophenyl)-2,4-dihydro-2,4-dimethyl-3Hl, 2,4-triazole-3-thione), an antidepressant drug, causes a dose-related thrombocytopenia in dogs. Platelet counts started to decline after two days of dosing with 30 mg/kg/day and continued to decrease to their lowest levels by 5-7 days. The loss in platelets was primarily of the small discoid subpopulation. In vitro studies have also indicated that MDL 19,660: does not spontaneously aggregate canine platelets and has moderate antiaggregating properties by inhibiting ADP-induced aggregation. The objectives of the present investigation of MDL 19,660 were to evaluate ultrastructurally long term effects on platelet internal architecture and changes in subpopulations of platelets and megakaryocytes.Nine male and nine female beagle dogs were divided equally into three groups and were administered orally 0, 15, or 30 mg/kg/day of MDL 19,660 for three months. Compared to a control platelet range of 353,000- 452,000/μl, a doserelated thrombocytopenia reached a maximum severity of an average of 135,000/μl for the 15 mg/kg/day dogs after two weeks and 81,000/μl for the 30 mg/kg/day dogs after one week.

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