Disposition of Vorinostat, A Novel Histone Deacetylase Inhibitor and Anticancer Agent, in Preclinical Species

Sandhu, Punam; Andrews, Paul A.; Baker, Maribeth P.; Koeplinger, Kenneth A.; Soli, Eric D.; Miller, Thomas A.; Baillie, Thomas A.

doi:10.2174/187231207780363642

Cited by 28 publications

(28 citation statements)

References 14 publications

(20 reference statements)

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“…Another HDAC inhibitor, kenedine 91, has extensive distribution that was attributed to its high lipid solubility. 30 High distribution of vorinostat to the liver as has been reported in other studies, 13 which may also account for the extensive distribution of the drug.…”

Section: Resultsmentioning

confidence: 67%

“…administration to rats at a dose of 2 mg/kg. 13 Extensive distribution of vorinostat in control formulation may be explained in part by its high tissue uptake due to its high lipid solubility. Another HDAC inhibitor, kenedine 91, has extensive distribution that was attributed to its high lipid solubility.…”

Section: Resultsmentioning

confidence: 99%

“…5,13,14,4,15 Much of the short half-life and limited overall exposure of vorinostat is related to its rapid metabolism, which is its predominate route of elimination. 13 Vorinostat is metabolized via two metabolic pathways including glucuronidation and hydrolysis followed by β-oxidation. These pathways produce two inactive metabolites, a vorinostat glucuronide and a vorinostat hydrolysis metabolite, 4-anilino-4-oxobutanoic acid, both of which are excreted in the urine.…”

Section: Introductionmentioning

confidence: 99%

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Vorinostat with sustained exposure and high solubility in poly(ethylene glycol)‐b‐poly(dl‐lactic acid) micelle nanocarriers: Characterization and effects on pharmacokinetics in rat serum and urine

Mohamed

Zhao

Meshali

et al. 2012

Journal of Pharmaceutical Sciences

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The histone deacetylase inhibitor suberoylanilide hydroxamic acid, known as vorinostat, is a promising anti-cancer drug with a unique mode of action; however, it is plagued by low water solubility, low permeability, and suboptimal pharmacokinetics. In this study, poly(ethylene glycol)-b-poly(DL-lactic acid) (PEG-b-PLA) micelles of vorinostat were developed. Vorinostat’s pharmacokinetics in rats were investigated after intravenous (i.v.) (10 mg/kg) and oral (50 mg/kg) micellar administrations and compared to a conventional PEG400 solution and methylcellulose suspension. The micelles increased the aqueous solubility of vorinostat from 0.2 mg/ml to 8.15 ± 0.60 mg/ml and 10.24 ± 0.92 mg/ml at drug to nanocarrier ratios of 1:10 and 1:15, respectively. Micelles had nanoscopic mean diameters of 75.67 ± 7.57 nm and 87.33 ± 8.62 nm for 1:10 and 1:15 micelles, respectively, with drug loading capacities of 9.93 ± 0.21% and 6.91 ± 1.19 %, and encapsulation efficiencies of 42.74 ± 1.67% and 73.29 ± 4.78%, respectively. The micelles provided sustained exposure and improved pharmacokinetics characterized by a significant increase in serum half-life, area under curve, and mean residence time. The micelles reduced vorinostat clearance particularly after i.v. dosing. Thus, PEG-b-PLA micelles significantly improved the oral and intravenous pharmacokinetics and bioavailability of vorinostat, which warrants further investigation.

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Section: Resultsmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Vorinostat with sustained exposure and high solubility in poly(ethylene glycol)‐b‐poly(dl‐lactic acid) micelle nanocarriers: Characterization and effects on pharmacokinetics in rat serum and urine

Mohamed

Zhao

Meshali

et al. 2012

Journal of Pharmaceutical Sciences

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“…It is possible that SB939, a hydroxamic acid, may also be cleared extrahepatically. Vorinostat and Givinostat, both hydroxamic acids, were cleared by metabolic and renal pathways in preclinical species (Sandhu et al, 2007;Furlan et al, 2011). Furthermore, in line with other hydroxamic acid functionalized HDAC inhibitors, which are known to undergo glucoronidation at the hydroxamic acid group, the formation of the glucuronide product of SB939 as a major Phase 2 metabolite was observed in rat urine.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Metabolism and Disposition of SB939 (Pracinostat), an Orally Active Histone Deacetylase Inhibitor, and Prediction of Human Pharmacokinetics

Jayaraman¹,

Reddy

Pasha³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The preclinical absorption, distribution, metabolism, and excretion (ADME) properties of Pracinostat [(2E)-3-[2-butyl-1-[2-(diethylamino) ethyl]-1H-benzimidazol-5-yl]-N-hydroxyarylamide hydrochloride; SB939], an orally active histone deacetylase inhibitor, were characterized and its human pharmacokinetics (PK) was predicted using Simcyp and allometric scaling. SB939 showed high aqueous solubility with high Caco-2 permeability. Metabolic stability was relatively higher in dog and human liver microsomes than in mouse and rat. The major metabolites formed in human liver microsomes were also observed in preclinical species. Human cytochrome P450 (P450) phenotyping showed that SB939 was primarily metabolized by CYP3A4 and CYP1A2. SB939 did not significantly inhibit human CYP3A4, 1A2, 2D6, and 2C9 (>25 M) but inhibited 2C19 (IC 50 ‫؍‬ 5.8 M). No significant induction of human CYP3A4 and 1A2 was observed in hepatocytes. Plasma protein binding in mouse, rat, dog, and human ranged between ϳ84 and 94%. The blood-toplasma ratio was ϳ1.0 in human blood. SB939 showed high systemic clearance (relative to liver blood flow) of 9.2, 4.5, and 1.5 l ⅐ h ؊1 ⅐ kg ؊1 and high volume of distribution at steady state (>0.6 l/kg) of 3.5, 1.7, and 4.2 l/kg in mouse, rat, and dog, respectively. The oral bioavailability was 34, 65, and ϳ3% in mice, dogs, and rats, respectively. The predicted oral PK profile and parameters of SB939, using Simcyp and allometric scaling, were in good agreement with observed data in humans. Simcyp predictions showed lack of CYP3A4 and 2C19 drug-drug interaction potential for SB939. In summary, the preclinical ADME of SB939 supported its preclinical and clinical development as an oral drug candidate.

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“…The CYP450 enzymes were not responsible for the biotransformation of Vorinostat (http://www.accessdata.fda). In preclinical studies in rats and dogs (Sandhu et al, 2007), the PK of Vorinostat was characterized by high systemic CL (7.8 and 3.3 L/h/kg in dog (> liver blood flow of ~ 1.9 L/h/kg) and rat (=liver blood flow of 3.3 L/h/kg), respectively), low to moderate V ss (1.6 and 0.6 L/kg in dog and rat respectively), short half-lives (12 min in dog and rat), and poor oral bioavailability (11 % and ~ 2% in dog and rat, respectively). The O-glucoronide and 4-AOB metabolites of Vorinostat were detected in significant levels in both the species following oral dosing (AUC ratio of O-glucoronide to Vorinostat was ~ 1.0 and 2.3 in dog and rat, respectively; and the AUC ratio of 4-AOB to Vorinostat was 10 and 23 in dog and rat, respectively).…”

Section: Entinostat (Ms-275)mentioning

confidence: 99%

Histone Deacetylase Inhibitors as Therapeutic Agents for Cancer Therapy: Drug Metabolism and Pharmacokinetic Properties

Ethirajulu¹,

Jayaraman²

2011

Drug Development - A Case Study Based Insight Into Modern Strategies

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Disposition of Vorinostat, A Novel Histone Deacetylase Inhibitor and Anticancer Agent, in Preclinical Species

Cited by 28 publications

References 14 publications

Vorinostat with sustained exposure and high solubility in poly(ethylene glycol)‐b‐poly(dl‐lactic acid) micelle nanocarriers: Characterization and effects on pharmacokinetics in rat serum and urine

Vorinostat with sustained exposure and high solubility in poly(ethylene glycol)‐b‐poly(dl‐lactic acid) micelle nanocarriers: Characterization and effects on pharmacokinetics in rat serum and urine

Preclinical Metabolism and Disposition of SB939 (Pracinostat), an Orally Active Histone Deacetylase Inhibitor, and Prediction of Human Pharmacokinetics

Histone Deacetylase Inhibitors as Therapeutic Agents for Cancer Therapy: Drug Metabolism and Pharmacokinetic Properties

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