Pharmacokinetics of tafamidis,a transthyretin amyloidosis drug,in rats |
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| Authors: | Kyeong-Ryoon Lee Jong-Woo Jeong Hun-Chan Hyun Eunseo Jang Sunjoo Ahn Sungwook Choi |
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| Affiliation: | 1. Life Science Research Institute, Daewoong Pharmaceutical, Korea,;2. Graduate School of New Drug Discovery and Development, Chungnam National University, Korea,;3. Bio &4. Drug Discovery Division, Korea Research Institute of Chemical Technology, Korea, and |
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| 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 (Vss) and half-life (T½) 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. |
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| Keywords: | Amyloidosis biliary excretion pharmacokinetics Tafamidis transthyretin Vyndaqel |
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