Liquid chromatography–tandem mass spectrometric assay for sorafenib and sorafenib–glucuronide in mouse plasma and liver homogenate and identification of the glucuronide metabolite

Sparidans, Rolf W.; Vlaming, Maria L. H.; Lagas, Jurjen S.; Schinkel, Afred H.; Schellens, Jan H.M.; Beijnen, Jos H.

doi:10.1016/j.jchromb.2008.12.026

Cited by 34 publications

(26 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sorafenib concentrations in DMEM (Invitrogen) cell culture medium, plasma samples, and brain homogenates were determined using a sensitive and specific liquid chromatography-tandem mass spectrometry assay (29).…”

Section: Drug Analysismentioning

confidence: 99%

Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

Lagas

Waterschoot

Sparidans

et al. 2010

Molecular Cancer Therapeutics

Self Cite

168

123

View full text Add to dashboard Cite

Sorafenib is a second-generation, orally active multikinase inhibitor that is approved for the treatment of patients with advanced renal cell carcinoma and patients with unresectable hepatocellular carcinoma. We studied active transport of sorafenib in MDCK-II cells expressing human P-glycoprotein (P-gp/ABCB1) or ABCG2 (breast cancer resistance protein) or murine Abcg2. Sorafenib was moderately transported by P-gp and more efficiently by ABCG2 and Abcg2. Because sorafenib is taken orally, we orally administered sorafenib to wild-type, Abcb1a/1b −/− , Abcg2 −/− , and Abcb1a/1b;Abcg2 −/− mice, completely lacking functional Abcb1a/1b, Abcg2, or both, respectively, and we studied plasma pharmacokinetics and brain accumulation. The systemic exposure on oral administration was not different among all strains. However, brain accumulation was 4.3-fold increased in Abcg2 −/− mice and 9.3-fold increased in Abcb1a/1b;Abcg2 −/− mice. Moreover, when wildtype mice were treated with sorafenib in combination with the dual P-gp and ABCG2 inhibitor elacridar, brain accumulation was similar to that observed for Abcb1a/1b;Abcg2 −/− mice. These results show that the brain accumulation of sorafenib is primarily restricted by ABCG2. This contrasts with previous studies using shared ABCG2 and P-gp substrates, which all suggested that P-gp dominates at the blood-brain barrier, and that an effect of ABCG2 is only evident when both transporters are absent. Interestingly, for sorafenib, it is the other way around, that is, ABCG2, and not P-gp, plays the dominant role in restricting its brain accumulation. Clinically, our findings may be relevant for the treatment of renal cell carcinoma patients with central nervous system relapses, as a dual ABCG2 and P-gp inhibitor might improve the central nervous system entry and thereby the therapeutic efficacy of sorafenib. Mol Cancer Ther; 9(2); 319-26. ©2010 AACR.

show abstract

Section: Drug Analysismentioning

confidence: 99%

Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

Lagas

Waterschoot

Sparidans

et al. 2010

Molecular Cancer Therapeutics

Self Cite

168

123

View full text Add to dashboard Cite

show abstract

“…Most often, these assays have been validated for plasma of human subjects [11][12][13][14][15][17][18][19][20]22,[24][25][26][29][30][31]. For erlotinib [11,12], imatinib [19][20][21], sunitinib [27] and sorafenib [23] a metabolite could be quantified simultaneously with the parent drugs. In most methods the protonated parent molecule is used in the selected reaction monitoring (SRM) mode using a triple quadrupole (QqQ) system, with a quadrupole-linear ion trap combination [15] as the only exception.…”

Section: Introductionmentioning

confidence: 99%

Liquid chromatography-tandem mass spectrometric assay for the light sensitive tyrosine kinase inhibitor axitinib in human plasma

Sparidans

Iusuf

Schinkel

et al. 2009

Journal of Chromatography B

Self Cite

View full text Add to dashboard Cite

“…Only a few methods for quantification of sorafenib in human or mouse plasma by highperformance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) [13][14][15] were reported so far. Although HPLC-MS/MS techniques require only small sample volumes and minimal sample preparation they are expensive and not generally available.…”

Section: Discussionmentioning

confidence: 99%

High-performance liquid chromatographic method for the determination of sorafenib in human serum and peritoneal fluid

Heinz

Kahle

Helle-Beyersdorf

et al. 2010

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

In clinical trials adverse events improve after dose reduction suggesting a dose-dependent toxicity. Given dose has a direct impact on the drug serum concentration, but the latter also can be influenced by multiple factors including interaction and metabolization. To enable the investigation of concentration related effects, an easy and sensitive assay for sorafenib drug monitoring is essential. Methods:A high performance liquid chromatography (HPLC) analysis involving an extraction with diethyl ether followed by separation on a Pinnacle™ DB C18 column and quantitation by UV absorbance at 260 nm was established. Sorafenib concentrations in samples of serum and peritoneal fluid have been determined. Results:The assay was validated for serum samples and is linear over the concentration range of 100 to 5000 ng/mL with a determination coefficient of >0.999. The limit of detection is 0.25 ng/mL. The intra-and inter-day coefficients of variation were below 3.03%. Sorafenib recovery in spiked probes of peritoneal fluid was above 85 %. Sorafenib concentrations in 44 serum samples and 14 probes of peritoneal fluid have been determined with a mean of 3328 and 1380 ng/mL respectively (standard deviation 2267 and 659 ng/ml). Conclusions:A sensitive and selective HPLC method for the determination of sorafenib in human serum was developed and also verified for peritoneal fluid. This method provides a useful tool for pharmacokinetic investigations as well as for therapeutic drug monitoring of sorafenib.

show abstract

Liquid chromatography–tandem mass spectrometric assay for sorafenib and sorafenib–glucuronide in mouse plasma and liver homogenate and identification of the glucuronide metabolite

Cited by 34 publications

References 11 publications

Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

Liquid chromatography-tandem mass spectrometric assay for the light sensitive tyrosine kinase inhibitor axitinib in human plasma

High-performance liquid chromatographic method for the determination of sorafenib in human serum and peritoneal fluid

Contact Info

Product

Resources

About