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. 2013 Mar;344(3):655-64.
doi: 10.1124/jpet.112.201475. Epub 2012 Dec 17.

Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases (V体育官网)

Rajendar K Mittapalli  1 , Shruthi Vaidhyanathan, Arkadiusz Z Dudek, William F Elmquist
Affiliations

Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases

Rajendar K Mittapalli et al. J Pharmacol Exp Ther. 2013 Mar.

Abstract (V体育平台登录)

Brain metastases are a common cause of death in stage IV metastatic melanoma. Dabrafenib is a BRAF (gene encoding serine/threonine-protein kinase B-Raf) inhibitor that has been developed to selectively target the valine 600 to glutamic acid substitution (BRAF(V600E)), which is commonly found in metastatic melanoma. Clinical trials with dabrafenib have shown encouraging results; however, the central nervous system distribution of dabrafenib remains unknown. Thus, the objective of the current study was to evaluate the brain distribution of dabrafenib in mice, and to see whether active efflux by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) restricts its delivery across the blood-brain barrier (BBB). In vitro accumulation studies conducted in Madin-Darby canine kidney II cells indicate that dabrafenib is an avid substrate for both P-gp and BCRP. Directional flux studies revealed greater transport in the basolateral to apical direction with corrected efflux ratios greater than 2 for both P-gp and Bcrp1 transfected cell lines VSports手机版. In vivo, the ratio of area under the concentration-time curve (AUC)(brain) to AUC(plasma) (K(p)) of dabrafenib after an i. v. dose (2. 5 mg/kg) was 0. 023, which increased by 18-fold in Mdr1 a/b(-/-)Bcrp1(-/-) mice to 0. 42. Dabrafenib plasma exposure was ∼2-fold greater in Mdr1 a/b(-/-)Bcrp1(-/-) mice as compared with wild-type with an oral dose (25 mg/kg); however, the brain distribution was increased by ~10-fold with a resulting K(p) of 0. 25. Further, compared with vemurafenib, another BRAF(V600E) inhibitor, dabrafenib showed greater brain penetration with a similar dose. In conclusion, the dabrafenib brain distribution is limited in an intact BBB model, and the data presented herein may have clinical implications in the prevention and treatment of melanoma brain metastases. .

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"V体育2025版" Figures

Fig. 1.
Fig. 1.
Chemical structure of dabrafenib (GSK2118436A).
Fig. 2.
Fig. 2.
In vitro cellular accumulation of dabrafenib. (A) The accumulation of prazosin (prototypical Bcrp probe substrate; positive control) and dabrafenib in MDCKII–wild-type and Bcrp1-transfected cell lines with and without Bcrp inhibitor Ko143 (0.2 µM). The accumulation of dabrafenib and vinblastine (probe substrate for P-gp) in MDR1 cells with and without P-gp inhibitor LY335979 (1 µM) is shown in (B). Data represent the mean ± S.D.; n = 6 for all data points. ***P < 0.001 compared with respective wild-type controls; #P < 0.001 compared with the untreated transfected cell line.
Fig. 3.
Fig. 3.
Competition assays using prototypical probe substrate molecules. Intracellular accumulation of [3H]-prazosin (PRZ; Bcrp probe substrate), [3H]-vinblastine (VBL; P-gp probe substrate) in Bcrp1-transfected (A) and MDR1-transfected (B) cell lines with increasing concentrations of dabrafenib from 0.1 to 50 µM. Ko: Bcrp inhibitor Ko143; LY: P-gp inhibitor LY335979. Data represent the mean ± S.D.; n = 3 for all data points. *P = 0.0439 compared with untreated wild-type cells; **P = 0.003 compared with untreated MDR1 cells.
Fig. 4.
Fig. 4.
Brain and plasma concentration versus time profiles of dabrafenib. Brain and plasma concentrations of dabrafenib after an i.v. dose of 2.5 mg/kg in FVB wild-type mice at 5, 15, 30, 60, and 120 minutes postdose. Brain concentrations of dabrafenib are significantly lower than plasma concentrations at all measured time points. Data represent the mean ± S.D.; n = 3–4. *P < 0.05; **P < 0.001; ***P < 0.0001.
Fig. 5.
Fig. 5.
Brain distribution of dabrafenib in FVB wild-type and Mdr1a/b−/−Bcrp1−/− mice. Plasma concentration versus time (A), brain concentration versus time (B), and brain-to-plasma concentration ratios (C) of dabrafenib in wild-type and Mdr1a/b−/−Bcrp1−/− mice after an i.v. dose of 2.5 mg/kg. Plasma and brain concentrations were determined using LC-MS/MS at 5, 15, 30, 60, and 120 minutes postdose of dabrafenib. Data represent the mean ± S.D.; n = 3–4. *P < 0.05; **P < 0.001; ***P < 0.0001.
Fig. 6.
Fig. 6.
Brain distribution of dabrafenib in FVB wild-type and Mdr1a/b−/−Bcrp1−/− mice after an oral dose. Plasma (A) and brain (B) concentration versus time profiles, and brain-to-plasma concentration ratios (C) of dabrafenib in wild-type and Mdr1a/b−/−Bcrp1−/− mice after an oral dose of 25 mg/kg. Plasma and brain concentrations were determined using LC-MS/MS at 15, 30, 60, 120, and 240 minutes postdose of dabrafenib. Data represent the mean ± S.D.; n = 3–4. *P < 0.05; **P < 0.001; ***P < 0.0001.
Fig. 7.
Fig. 7.
Comparison of the brain distribution of dabrafenib and vemurafenib. Plasma (A), brain (B), and brain-to-plasma concentration ratios (C) of dabrafenib and vemurafenib in wild-type and Mdr1a/b−/−Bcrp1−/− mice after 1 hour postdose in separate animals (25 mg/kg, oral dose). Vemurafenib data are from our previously published results (Mittapalli et al., 2012). Data represent the mean ± S.D.; n = 3–4. *P < 0.05; **P < 0.001; ***P < 0.0001.
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