In Vitro Characterization of the Metabolic Pathways and Cytochrome P450 Inhibition and Induction Potential of BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor

Hong, Haizheng; Su, Hong; Ma, Li; Yao, Ming; Iyer, Ramaswamy A.; Humphreys, W. Griffith; Christopher, Lisa J.

doi:10.1124/dmd.111.039776

Cited by 10 publications

(14 citation statements)

References 30 publications

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“…For the purpose of simulations, all unidentified radioactivity in the human ADME study was assigned to metabolite M1. This assumption is reasonable because M1 is a major metabolite in vitro but is chemically unstable.10 Leveraging with in vitro reaction phenotyping data, the fraction of CYP and UGT enzymes to the total metabolism of BMS‐690514 was defined. The results obtained from HLM using selective chemical inhibitors were comparable with those from recombinant CYP systems.…”

Section: Discussionmentioning

confidence: 99%

“…For the renal and biliary clearance of the unchanged drug, the observed data were used as inputs to Simcyp and were assumed to be mediated by efflux transporters such as P‐gp. Evaluation of the metabolic clearance was complicated by the fact that the same metabolite was formed by multiple enzymes . For CYP enzymes, the contributions of CYP3A4, CYP2D6, and CYP2D6 to each metabolic pathway were evaluated based on in vitro reaction phenotyping data generated from HLM and recombinant CYP systems.…”

Section: Methodsmentioning

confidence: 98%

“…It is also actively secreted into the urine and bile as unchanged drug, with the renal clearance about 5 times higher than the plasma free fraction—corrected glomerular filtration rate . In vitro reaction phenotyping experiments demonstrate that cytochrome P450 (CYP) enzymes CYP3A4, CYP2D6, and CYP2C9 are the major enzymes responsible for the oxidative metabolism of BMS‐690514, whereas uridine diphosphate glucuronosyl transferase (UGT) enzymes UGT2B4 and UGT2B7 catalyze the glucuronidation reaction . Among these drug‐metabolizing enzymes, CYP3A4 accounted for the largest portion (~34%) of BMS‐690514 metabolism (Supplementary Figure S1).…”

mentioning

confidence: 99%

“…10 In vitro reaction phenotyping experiments demonstrate that cytochrome P450 (CYP) enzymes CYP3A4, CYP2D6, and CYP2C9 are the major enzymes responsible for the oxidative metabolism of BMS-690514, whereas uridine diphosphate glucuronosyl transferase (UGT) enzymes UGT2B4 and UGT2B7 catalyze the glucuronidation reaction. 11 Among these drug-metabolizing enzymes, CYP3A4 accounted for the largest portion (~34%) of BMS-690514 metabolism (Supplementary Figure S1). In addition, consistent with the renal and biliary active secretion observed in vivo, BMS-690514 is a substrate of efflux transporters, such as P-gp, in vitro.…”

mentioning

confidence: 99%

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Inhibitory Effect of Ketoconazole on the Pharmacokinetics of a Multireceptor Tyrosine Kinase Inhibitor BMS‐690514 in Healthy Participants: Assessing the Mechanism of the Interaction With Physiologically‐Based Pharmacokinetic Simulations

Yang¹,

Vakkalagadda²,

Shen³

et al. 2013

The Journal of Clinical Pharma

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BMS-690514, a selective inhibitor of the ErbB and vascular endothelial growth factor receptors, has shown antitumor activity in early clinical development. The compound is metabolized by multiple enzymes, with CYP3A4 responsible for the largest fraction (34%) of metabolism. It is also a substrate of P-glycoprotein (P-gp) in vitro. To assess the effect of ketoconazole on BMS-690514 pharmacokinetics, 17 healthy volunteers received 200 mg BMS-690514 alone followed by 100 mg BMS-690514 with ketoconazole (400 mg once daily for 4 days). The AUC(∞) of 100 mg BMS-690514 concomitantly administered with ketoconazole was similar to that of 200 mg BMS-690514 alone. The dose-normalized C(max) and AUC(∞) of BMS-690514 from the 100-mg BMS-690514/400-mg ketoconazole treatment increased by 55% and 127%, respectively, relative to those from 200 mg BMS-690514 alone. Prediction of the drug-drug interaction (DDI) using a population-based simulator (Simcyp) indicated that, in addition to CYP3A4 inhibition, the inhibition of P-gp by ketoconazole in the intestine, liver, and kidneys must be invoked to fully account for the DDI observed. This finding suggests that the inhibition of P-gp by ketoconazole, along with its effect on CYP3A4, needs to be considered when designing a DDI study of ketoconazole with a victim drug that is a dual substrate.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibitory Effect of Ketoconazole on the Pharmacokinetics of a Multireceptor Tyrosine Kinase Inhibitor BMS‐690514 in Healthy Participants: Assessing the Mechanism of the Interaction With Physiologically‐Based Pharmacokinetic Simulations

Yang¹,

Vakkalagadda²,

Shen³

et al. 2013

The Journal of Clinical Pharma

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“…The potential of saxagliptin and M2 to induce the expression of mRNA levels and/or P450 enzyme activity of CYP1A2, -2B6, and -3A4 was investigated in primary cultures of freshly isolated human hepatocytes, as described previously (Hong et al, 2011). Human hepatocytes isolated from three individual donors (lots Hu 211, Hu 223, and Hu 224; CellzDirect) were used.…”

Section: Lc-ms/ms Methods For Quantification Of M2 In In Vitromentioning

confidence: 99%

Characterization of the In Vitro and In Vivo Metabolism and Disposition and Cytochrome P450 Inhibition/Induction Profile of Saxagliptin in Human

Boulton²,

Barros³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Saxagliptin is a potent dipeptidyl peptidase-4 inhibitor approved for the treatment of type 2 diabetes mellitus. The pharmacokinetics and disposition of [ 14 C]saxagliptin were investigated in healthy male subjects after a single 50-mg (91.5 Ci) oral dose. Saxagliptin was rapidly absorbed (T max , 0.5 h). Unchanged saxagliptin and 5-hydroxy saxagliptin (M2), a major, active metabolite, were the prominent drug-related components in the plasma, together accounting for most of the circulating radioactivity. Approximately 97% of the administered radioactivity was recovered in the excreta within 7 days postdose, of which 74.9% was eliminated in the urine and 22.1% was excreted in the feces. The parent compound and M2 represented 24.0 and 44.1%, respectively, of the radioactivity recovered in the urine and feces combined. Taken together, the excretion data suggest that saxagliptin was well absorbed and was subsequently cleared by both urinary excretion and metabolism; the formation of M2 was the major metabolic pathway. Additional minor metabolic pathways included hydroxylation at other positions and glucuronide or sulfate conjugation. Cytochrome P450 (P450) enzymes CYP3A4 and CYP3A5 metabolized saxagliptin and formed M2. Kinetic experiments indicated that the catalytic efficiency (V max /K m ) for CYP3A4 was approximately 4-fold higher than that for CYP3A5. Therefore, it is unlikely that variability in expression levels of CYP3A5 due to genetic polymorphism will impact clearance of saxagliptin. Saxagliptin and M2 each showed little potential to inhibit or induce important P450 enzymes, suggesting that saxagliptin is unlikely to affect the metabolic clearance of coadministered drugs that are substrates for these enzymes.

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A phase I trial to determine the safety, pharmacokinetics, and pharmacodynamics of intercalated BMS-690514 with paclitaxel/carboplatin (PC) in advanced or metastatic solid malignancies

Chow

Jonker

et al. 2013

Cancer Chemother Pharmacol

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In Vitro Characterization of the Metabolic Pathways and Cytochrome P450 Inhibition and Induction Potential of BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor

Cited by 10 publications

References 30 publications

Inhibitory Effect of Ketoconazole on the Pharmacokinetics of a Multireceptor Tyrosine Kinase Inhibitor BMS‐690514 in Healthy Participants: Assessing the Mechanism of the Interaction With Physiologically‐Based Pharmacokinetic Simulations

Inhibitory Effect of Ketoconazole on the Pharmacokinetics of a Multireceptor Tyrosine Kinase Inhibitor BMS‐690514 in Healthy Participants: Assessing the Mechanism of the Interaction With Physiologically‐Based Pharmacokinetic Simulations

Characterization of the In Vitro and In Vivo Metabolism and Disposition and Cytochrome P450 Inhibition/Induction Profile of Saxagliptin in Human

A phase I trial to determine the safety, pharmacokinetics, and pharmacodynamics of intercalated BMS-690514 with paclitaxel/carboplatin (PC) in advanced or metastatic solid malignancies

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