Pharmacokinetics, Distribution, and Metabolism of [<sup>14</sup>C]Sunitinib in Rats, Monkeys, and Humans

Speed, Bill; Bu, Hai‐Zhi; Pool, William F.; Peng, Geoffrey W.; Wu, Ellen; Patyna, Shem; Bello, Carlo L.; Kang, Ping

doi:10.1124/dmd.111.042853

Cited by 86 publications

(106 citation statements)

References 19 publications

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“…1), an oral tyrosine kinase inhibitor, is primarily metabolized by CYP3A4; it displayed conserved and consistent dmd.aspetjournals.org metabolic profiles across human, monkey, dog, and rat MPCC hepatocytes generating the N-desethyl metabolite (1a) in agreement with known in vivo data (Supplemental Fig. 1) (FDA, 2006;Speed et al, 2012). An N-oxide metabolite (1b), although not major in human in vivo, is also conserved across human, monkey, dog and rat MPCC hepatocytes, and the results were comparable to the in vivo metabolite profiles (Supplemental Fig.…”

Section: Resultssupporting

confidence: 71%

Application of a Micropatterned Cocultured Hepatocyte System To Predict Preclinical and Human-Specific Drug Metabolism

Ballard

Wang

Cox

et al. 2015

Drug Metabolism and Disposition

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Laboratory animal models are the industry standard for preclinical risk assessment of drug candidates. Thus, it is important that these species possess profiles of drug metabolites that are similar to those anticipated in human, since metabolites also could be responsible for biologic activities or unanticipated toxicity. Under most circumstances, preclinical species reflect human in vivo metabolites well; however, there have been several notable exceptions, and understanding and predicting these exceptions with an in vitro system would be very useful. Human micropatterned cocultured (MPCC) hepatocytes have been shown to recapitulate human in vivo qualitative metabolic profiles, but the same demonstration has not been performed yet for laboratory animal species. In this study, we investigated several compounds that are known to produce human-unique metabolites through CYP2C9, UGT1A4, aldehyde oxidase (AO), or N-acetyltransferase that were poorly covered or not detected at all in the selected preclinical species. To perform our investigation we used 24-well MPCC hepatocyte plates having three individual human donors and a single donor each of monkey, dog, and rat to study drug metabolism at four time points per species. Through the use of the multispecies MPCC hepatocyte system, the metabolite profiles of the selected compounds in human donors effectively captured the qualitative in vivo metabolite profile with respect to the human metabolite of interest. Human-unique metabolites that were not detected in vivo in certain preclinical species (normally dog and rat) were also not generated in the corresponding species in vitro, confirming that the MPCC hepatocytes can provide an assessment of preclinical species metabolism. From these results, we conclude that multispecies MPCC hepatocyte plates could be used as an effective in vitro tool for preclinical understanding of species metabolism relative to humans and aid in the choice of appropriate preclinical models.

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Section: Resultssupporting

confidence: 71%

Application of a Micropatterned Cocultured Hepatocyte System To Predict Preclinical and Human-Specific Drug Metabolism

Ballard

Wang

Cox

et al. 2015

Drug Metabolism and Disposition

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“…15 However, the concentration of its active metabolite N-desethyl sunitinib was markedly higher, indicating increased metabolism of the parent compound in rats, as reported previously. 18 Glomerular endotheliosis, sometimes accompanied by thrombi, is a hallmark of angiogenesis inhibition-induced renal injury. 5 In this study, glomerular endotheliosis with almost complete obliteration of glomerular capillaries was observed at the highest dose of sunitinib, whereas endotheliosis was less severe with the intermediate and absent with the low dose of sunitinib.…”

Section: Discussionmentioning

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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“…According to the in vitro data, the complete delivery of sunitinib in tissues is obtained one day following the embolization with REM. Then, upon drug delivery we suppose a rapid decay of sunitinib concentration in tissue according to biodistribution studies showing that sunitinib remained in most of organs only 72 h after administration (Speed et al, 2012). After its local delivery from REM, sunitinib could exert both anti-angiogenic and cytotoxic effects.…”

Section: Sunitinibmentioning

confidence: 99%

Anti-angiogenic drug delivery from hydrophilic resorbable embolization microspheres: An in vitro study with sunitinib and bevacizumab

Bédouet¹,

Verret²,

Louguet³

et al. 2015

International Journal of Pharmaceutics

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Pharmacokinetics, Distribution, and Metabolism of [¹⁴C]Sunitinib in Rats, Monkeys, and Humans

Cited by 86 publications

References 19 publications

Application of a Micropatterned Cocultured Hepatocyte System To Predict Preclinical and Human-Specific Drug Metabolism

Application of a Micropatterned Cocultured Hepatocyte System To Predict Preclinical and Human-Specific Drug Metabolism

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

Anti-angiogenic drug delivery from hydrophilic resorbable embolization microspheres: An in vitro study with sunitinib and bevacizumab

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Pharmacokinetics, Distribution, and Metabolism of [14C]Sunitinib in Rats, Monkeys, and Humans

Cited by 86 publications

References 19 publications

Application of a Micropatterned Cocultured Hepatocyte System To Predict Preclinical and Human-Specific Drug Metabolism

Application of a Micropatterned Cocultured Hepatocyte System To Predict Preclinical and Human-Specific Drug Metabolism

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

Anti-angiogenic drug delivery from hydrophilic resorbable embolization microspheres: An in vitro study with sunitinib and bevacizumab

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Pharmacokinetics, Distribution, and Metabolism of [¹⁴C]Sunitinib in Rats, Monkeys, and Humans