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Pharmacokinetics of tafamidis, a transthyretin amyloidosis drug, in rats.
- Source :
-
Xenobiotica; the fate of foreign compounds in biological systems [Xenobiotica] 2018 Aug; Vol. 48 (8), pp. 831-838. Date of Electronic Publication: 2017 Nov 16. - Publication Year :
- 2018
-
Abstract
- 1. We characterized the pharmacokinetics of tafamidis, a novel drug to treat transthyretin-related amyloidosis, in rats after intravenous and oral administration at doses of 0.3-3 mg/kg. In vitro Caco-2 cell permeability and liver microsomal stability, as well as in vivo tissue distribution and plasma protein binding were also examined. 2. After intravenous injection, systemic clearance (CL), volumes of distribution at steady state (V <subscript>ss</subscript> ) and half-life (T <subscript>½</subscript> ) remained unaltered as a function of dose, with values in the ranges of 6.41-7.03 mL/h/kg, 270-354 mL/kg and 39.5-46.9 h, respectively. Following oral administration, absolute bioavailability was 99.7-104% and was independent of doses from 0.3 to 3 mg/kg. In the urine and faeces, 4.36% and 48.9% of tafamidis, respectively, were recovered. 3. Tafamidis was distributed primarily in the liver and not in the brain, kidney, testis, heart, spleen, lung, gut, muscle, or adipose tissue. Further, tafamidis was very stable in rat liver microsomes, and its plasma protein binding was 99.9%. 4. In conclusion, tafamidis showed dose-independent pharmacokinetics with intravenous and oral doses of 0.3-3 mg/kg. Tafamidis undergoes minimal first-pass metabolism, distributes mostly in the liver and plasma, and appears to be eliminated primarily via biliary excretion.
- Subjects :
- Animals
Brain pathology
Caco-2 Cells
Humans
Liver pathology
Male
Microsomes, Liver metabolism
Microsomes, Liver pathology
Organ Specificity
Rats
Rats, Sprague-Dawley
Amyloid Neuropathies, Familial drug therapy
Amyloid Neuropathies, Familial metabolism
Amyloid Neuropathies, Familial pathology
Benzoxazoles pharmacokinetics
Benzoxazoles pharmacology
Brain metabolism
Liver metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1366-5928
- Volume :
- 48
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Xenobiotica; the fate of foreign compounds in biological systems
- Publication Type :
- Academic Journal
- Accession number :
- 28803538
- Full Text :
- https://doi.org/10.1080/00498254.2017.1366575