Sorafenib (Brand name: Nexavar, BAY 43-9006) is an oral anti-cancer drug approved by the U.S. Food and Drug Administration for the treatment of advanced renal cell carcinoma (December 2005) and unresectable hepatocellular carcinoma (November 2007). The small molecule multikinase inhibitor blocks tumor cell proliferation and angiogenesis by targeting various types of serine/threonine and receptor tyrosine kinases. Sorafenib is also in clinical trials for the treatment of thyroid, lung, and recurrent glioblastoma cancers. While the drug is generally well-tolerated, some adverse effects include skin rash, diarrhea, and hypertension.
Sorafenib is a low-solubility, high permeability compound. After oral administration, sorafenib is rapidly absorbed, resulting in peak plasma levels within 3 hours [Article:16006586]. Upon multiple dosing of the drug for 7 days, a 2.5- to 7-fold accumulation of sorafenib is observed compared to a single dose administration with steady-state plasma concentrations of the drug reached and a peak-to-trough ratio of mean concentrations less than 2. The relative bioavailability of sorafenib tablets compared to an oral solution is 38 - 49%. However, in the presence of a high-fat meal, the bioavailability of sorafenib decreases by 29% compared to administration with a moderate-fat meal or in a fasted state. Elimination of the drug primarily occurs in the liver through Cytochrome P450 3A4 (CYP3A4) mediated oxidative metabolism, or glucuronidation by UDP glucuronosyltransferase 1-9 (UGT1A9) [Articles:17189398, 22307138]. Eight metabolites of sorafenib have been identified (M1-8), with five of these metabolites detected in the plasma (M2, M3, M4, M6, M7), three in the feces (M3, M4, M6) with M6 (carboxylic acid) as the major metabolite (19.1% of the administered dose), and two in the urine (M7, M8). The main circulating metabolite in the plasma, which is produced through oxidation of sorafenib by CYP3A4, is sorafenib-N-oxide (M2) [Articles:19733976, 22307138]. Comprising 9 - 16% of the circulating analytes at steady-state, M2 exhibits an in vitro potency similar to sorafenib. M2 also gets further metabolized to M1 (combination of M2 and N-methylhydroxylation (M3)) and glucuronidation to M8 (glucuronide of M2). The metabolite M7 (glucuronide of sorafenib) is produced through glucuronidation of the parent compound by UGT1A9. Among the metabolites of sorafenib, M2, M4 (demethylation), and M5 (oxidative metabolite) were found to inhibit VEGFR and PDGFR signaling pathways and members of the Raf/Mek/Erk pathway. Finally, after a 100 mg oral administration of sorafenib, 96% of the dose is recovered within 14 days with 77% of the drug excreted in the feces, 19% excreted as glucuronidated metabolites in the urine, and due to either inefficient metabolism or lack of intestinal absorption, 50% from the feces as unchanged drug [Article:17189398]. The volume of distribution of the drug has not been reported, however, sorafenib is highly protein bound (~99.5%) and has an average half-life of 25 - 48 hours, suggesting the drug may have a large volume of distribution [Articles:15613696, 19733976].
Sorafenib has been demonstrated to be a weak substrate of several membrane transporters. In an in vitro study involving Xenopus laevis oocytes or HEK293 cells transfected with transporters from the SLC22A and SLCO family of transporters (OATP1A2, OATP1B1, OATP1B3, OCT1, OCT2, OCTN1, OCTN2), sorafenib did not appear to be a substrate of these transporters PIMD: 19773380. However, sorafenib was demonstrated to have a moderate affinity for several members of the ABC membrane transporter family have been shown to interact with sorafenib. In LLC_PK1, Caco-2, K562, and MDCKII cells, sorafenib demonstrated to be a moderate substrate for the efflux transporter ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) [Articles:19773380, 20413726, 20446917, 20103600]. Sorafenib was also demonstrated to be a substrate of ABCG2 and perhaps, ABCB1, in vivo. Mice completely lacking both functional ABCB1 and ABCB2 had a higher accumulation of sorfaenib in the brain upon oral administration of sorafenib than mice lacking either of the transporters alone. While systemic exposure was not different between the strains, the in vivo data suggested that sorafenib appeared to be a better substrate for Abcg2 than Abcg1. While several studies demonstrate that sorafenib is a weak substrate of P-gp and BCRP, there is also data suggesting that higher concentrations of sorafenib (>1 uM) results in an autoinhibitory effect on ABCB1, ABCG2, ABCC2, and ABCC4 [Articles:19773380, 20952483]. Finally, the glutathione-conjugate (GS-E) transporter, RLIP76, has been shown to mediate transport of sorafenib, resulting in drug resistance in kidney cancer [Article:19626587]
Sorafenib inhibits CYP2B6, CYP2C8 and CYP2C9 in vitro, as well as UGT1A1[Articles:19228077, 22307138]. The clinical significance of these inhibition is not clear and drugs that are metabolized by these enzyme should also be used with caution in patients receiving sorafenib due to a potential risk of drug interactions.
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
Entities in the Pathway
Drugs/Drug Classes (1)
Relationships in the Pathway
|Arrow From||Arrow To||Controllers||PMID|
|Pyridine N-oxide (M2)||M1||16133532|
|sorafenib||glucuronide of sorafinib||UGT1A9||16133532, 22307138|
|sorafenib||Pyridine N-oxide (M2)||CYP3A4||19228077|
|Pyridine N-oxide (M2)||glucuronide of M2||19228077|
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