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EC number: 608-209-4 | CAS number: 284461-73-0
Summary on pharmacokinetic results of BAY 43-9006 (sorafenib):
Pharmacokinetics of sorafenib administered as its tosylate salt, BAY 54-9085, was investigated in vivoin Wistar rats, CD-1 mice, and in Beagle dogs. Additionally, in vitro studies were performed to investigate plasma protein binding, blood cell/plasma partitioning, and drug metabolism in several species including humans.
After oral administration of (14C)-labeled sorafenib tosylate the absorption of radioactivity (unchanged compound and radioactive metabolites) from the gastrointestinal tract was almost complete in rats and mice and was limited in dogs (68%). The absolute bioavailability of the unchanged compound was moderate to high amounting to 60% in dogs and to 80 % in rats and mice.
Plasma clearance in rats (0.044 L / (kg x h)) was markedly lower than in mice and dogs (0.13 - 0.15 L / (kg x h)). The volume of distribution at steady state was moderate, amounting to about 0.7 L / kg for rats, mice,and dogs. The plasma elimination half-lives of the unchanged substance were about 9 hours in rats, 6 hours in mice, and 4 hours in dogs, and were independent from the route of administration.
The protein binding of sorafenib was high and species-dependent. Albumin was identified as an important binding component in human plasma. In tissue distribution studies, radioactivity was rapidly and homogeneously distributed to almost all organs and tissues. Blood/brain penetration was low to moderate. There was no evidence of irreversible binding or retention of radioactivity in organs and tissues of rats. 14C-sorafenib and/or its radio-labeled metabolites penetrated the placental barrier to a moderate extent and were markedly secretedinto the milk of lactating rats.
Sorafenib exhibited no inductive potential on major CYP isoforms (CYP1A2 and 3A4). Sorafenib showed apotency to inhibit CYP isoforms (e.g., CYP2B6, 2C8, and 2C9) and UDP-glucuronosyltransferases UGT1A1 and UGT1A9in vitro. In vitro species comparison based on liver microsomal incubations revealed N-oxidation (M-2) to be prominent in humans, monkeys, and mice, whereas rats and dogs preferentially formed M-3 by N-methyl hydroxylation. Cytochrome P450 3A4 is the enzyme responsible for Phase I reactions (oxidative metabolism) of sorafenib in humans. In addition to Phase I reactions, human hepatocytes were capable of forming sorafenib glucuronide(M-7). Glucuronidation of sorafenib was catalyzed by UGT1A9.
Following oral administration, the unchanged compound was the major component in rat,dog, and human plasma. In rat and dog plasma, M-3 was a main metabolite, whereas in human plasma, M-2 was prominent. In humans, total plasma radioactivity and sorafenib are subject to enterohepatic circulation. Sorafenib was a major component in feces extracts of humans and rats. The carboxylic acid M-6 was a main metabolite in feces of rats, dogs, and humans. Comparison of the biotransformation of sorafenib in humans and animals revealed significant differences in Phase II reactions as well as in Phase I reactions in vitro and in vivo. In humans, N-oxidation of the pyridine (M-2) was much more pronounced than methylhydroxylation (M-3) in vitro and in vivo. Glucuronidation only played an important role in the biotransformation of sorafenib in humans.
Renal excretion of radioactivity was more pronounced in humans than in rats and dogs due to species-dependent formation of M-7 sorafenib glucuronide, which was excreted into human urine. In rats and dogs, the radioactivity was excreted mainly via the biliary/fecal route; urinary excretion was low. In rats, the radioactivity was almost completely excreted 72 hours after dosing.
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