Bioanalytical method for the quantification of sunitinib and its n-desethyl metabolite SU12662 in human plasma by ultra performance liquid chromatography/tandem triple-quadrupole mass spectrometry

Bruijn, Peter de; Sleijfer, Stefan; Lam, Mei-Ho; Mathijssen, Ron H.J.; Wiemer, Erik A.C.; Loos, Walter J.

doi:10.1016/j.jpba.2009.10.020

Cited by 52 publications

(40 citation statements)

References 16 publications

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“…All mice were administered 20 mg/kg by oral gavage and were euthanized using a carbon dioxide chamber at the desired time point. Since sunitinib exhibits light-sensitive diastereoisomerism (de Bruijn et al, 2010), all experiments and sample analyses were performed under light-protected conditions.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Assessment of Efflux Transport in Sunitinib Distribution to the Brain

Oberoi

Mittapalli

Elmquist

2013

J Pharmacol Exp Ther

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This study quantitatively assessed transport mechanisms that limit the brain distribution of sunitinib and investigated adjuvant strategies to improve its brain delivery for the treatment of glioblastoma multiforme (GBM). Sunitinib has not shown significant activity in GBM clinical trials, despite positive results seen in preclinical xenograft studies. We performed in vivo studies in transgenic Friend leukemia virus strain B mice: wild-type, Mdr1a/b(2/2), Bcrp1(2/2), and Mdr1a/b(2/2)Bcrp1(2/2) genotypes were examined. The brain-to-plasma area under the curve ratio after an oral dose (20 mg/kg) was similar to the steady-state tissue distribution coefficient, indicating linear distribution kinetics in mice over this concentration range. Furthermore, the distribution of sunitinib to the brain increased after administration of selective P-glycoprotein (P-gp) or breast cancer resistance protein (Bcrp) pharmacological inhibitors and a dual inhibitor, elacridar, comparable to that of the corresponding transgenic genotype. The brain-to-plasma ratio after coadministration of elacridar in wild-type mice was ∼12 compared with ∼17.3 in Mdr1a/b(2/2)Bcrp1(2/2) mice. Overall, these findings indicate that there is a cooperation at the blood-brain barrier (BBB) in restricting the brain penetration of sunitinib, and brain delivery can be enhanced by administration of a dual inhibitor. These data indicate that the presence of cooperative efflux transporters, P-gp and Bcrp, in an intact BBB can protect invasive glioma cells from chemotherapy. Thus, one may consider the use of transporter inhibition as a powerful adjuvant in the design of future clinical trials for the targeted delivery of sunitinib in GBM.

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Assessment of Efflux Transport in Sunitinib Distribution to the Brain

Oberoi

Mittapalli

Elmquist

2013

J Pharmacol Exp Ther

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“…Sunitinib levels were measured by a validated ultraperformance liquid chromatography/ tandem mass spectrometry system, at the laboratory of Translational Pharmacology of the Erasmus MC Cancer Institute. 13 …”

Section: Biochemical Measurementsmentioning

confidence: 99%

Greater Sensitivity of Blood Pressure Than Renal Toxicity to Tyrosine Kinase Receptor Inhibition With Sunitinib

et al. 2015

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Abstract-Hypertension and renal injury are off-target effects of sunitinib, a tyrosine kinase receptor inhibitor used for the treatment of various tumor types. Importantly, these untoward effects are accompanied by activation of the endothelin system. Here, we set up a study to explore the dose dependency of these side effects. Normotensive Wistar Kyoto rats were exposed to 3 different doses of sunitinib or vehicle. After 8 days, rats were euthanized. Telemetrically measured blood pressure rose dose dependently, from 13 to 30 mm Hg. Proteinuria was present at all doses, but a rise in cystatin C occurred only at the intermediate and high doses. Compared with vehicle circulating endothelin-1 increased dose dependently, whereas 24-hour urinary endothelin excretion decreased. Light and electron microscopy revealed glomerular endotheliosis and ischemia with the intermediate and high doses of sunitinib but completely absent histological abnormalities with the low dose. Podocyte number per glomerular circumference did not change. Glomerular nephrin, Neph1, podocin, and endothelin-converting enzyme gene expression were downregulated in a dose-dependent manner.We conclude that the sunitinib-induced rise in blood pressure requires lower doses than its induction of renal function impairment and that functional changes in glomerular filtration barrier contribute to the occurrence of proteinuria, given the lack of histopathologic changes with the low dose of sunitinib. (Hypertension. 2015;66:543-549.

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“…Sunitinib levels were measured by a validated ultraperformance liquid chromatography/tandem mass spectrometry system. 16 …”

Section: Biochemical Measurementsmentioning

confidence: 99%

Treatment of Hypertension and Renal Injury Induced by the Angiogenesis Inhibitor Sunitinib

et al. 2014

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Abstract-Common adverse effects of angiogenesis inhibition are hypertension and renal injury. To determine the most optimal way to prevent these adverse effects and to explore their interdependency, the following drugs were investigated in unrestrained Wistar Kyoto rats exposed to the angiogenesis inhibitor sunitinib: the dual endothelin receptor antagonist macitentan; the calcium channel blocker amlodipine; the angiotensin-converting enzyme inhibitor captopril; and the phosphodiesterase type 5 inhibitor sildenafil. Mean arterial pressure was monitored telemetrically. After 8 days, rats were euthanized and blood samples and kidneys were collected. In addition, 24-hour urine samples were collected. After sunitinib start, mean arterial pressure increased rapidly by ≈30 mm Hg. Coadministration of macitentan or amlodipine largely prevented this rise, whereas captopril or sildenafil did not. Macitentan, captopril, and sildenafil diminished the sunitinib-induced proteinuria and endothelinuria and glomerular intraepithelial protein deposition, whereas amlodipine did not. Changes in proteinuria and endothelinuria were unrelated. We conclude that in our experimental model, dual endothelin receptor antagonism and calcium channel blockade are suitable to prevent angiogenesis inhibitioninduced hypertension, whereas dual endothelin receptor antagonism, angiotensin-converting enzyme inhibitor, and phosphodiesterase type 5 inhibition can prevent angiogenesis inhibition-induced proteinuria. Moreover, the variable response of hypertension and renal injury to different antihypertensive agents suggests that these side effects are, at least

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Bioanalytical method for the quantification of sunitinib and its n-desethyl metabolite SU12662 in human plasma by ultra performance liquid chromatography/tandem triple-quadrupole mass spectrometry

Cited by 52 publications

References 16 publications

Pharmacokinetic Assessment of Efflux Transport in Sunitinib Distribution to the Brain

Pharmacokinetic Assessment of Efflux Transport in Sunitinib Distribution to the Brain

Greater Sensitivity of Blood Pressure Than Renal Toxicity to Tyrosine Kinase Receptor Inhibition With Sunitinib

Treatment of Hypertension and Renal Injury Induced by the Angiogenesis Inhibitor Sunitinib

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