Reaction phenotyping of vinblastine metabolism in dogs

Achanta, Satyanarayana; Maxwell, Lara K.

doi:10.1111/vco.12084

Cited by 5 publications

(7 citation statements)

References 35 publications

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“…The PBPK model presented here is distinct as it is a first‐generation VBL model that was successfully extrapolated from mouse to canine and human. The predictive model is governed by the well‐established drivers of vinca distribution and elimination: (a) intracellular tubulin binding 2 , 12 , 58 (b) high plasma protein binding, specifically to alpha1‐acid glycoprotein 59 (c) ABCB1‐mediated transport 16 , 40 , 60 (d) metabolism by isoforms of cytochrome P450 enzyme, CYP3A4, 19 and CYP3A12 20 in humans and dogs, respectively, and (e) elimination through glomerular filtration and biliary excretion. 5 The predominantly flow‐limited PBPK model, consisting of nine distinct compartments, was first developed in wild‐type and Mdr1a/b(−/−) mice.…”

Section: Discussionmentioning

confidence: 99%

“… 38 b Michaelis–Menten parameters used in dog and human models sourced from experimental studies using dog liver microsomes. 20 Kinetic parameters estimated using nonlinear regression fitting of Web‐Plot digitized data and extrapolated using 55 mg protein/g liver for in vitro‐in vivo scaling. 39 c Optimized Michaelis–Menten parameters for ABCB1 activity and biliary excretion.…”

Section: Methodsmentioning

confidence: 99%

“…Metabolism of VBL is primarily attributed to the CYP3A family of enzymes, specifically CYP3A4 and CYP3A12 in humans 19 and canines, 20 respectively. The primary metabolite of VBL identified in humans and dogs is the active 4‐deacetylvinblastine and has been reported to have a LD 50 lower than that of the parent 21 .…”

Section: Introductionmentioning

confidence: 99%

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Vinblastine pharmacokinetics in mouse, dog, and human in the context of a physiologically based model incorporating tissue‐specific drug binding, transport, and metabolism

Witta

Collins

Ramirez

et al. 2023

Pharmacology Res & Perspec

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Vinblastine (VBL) is a vinca alkaloid‐class cytotoxic chemotherapeutic that causes microtubule disruption and is typically used to treat hematologic malignancies. VBL is characterized by a narrow therapeutic index, with key dose‐limiting toxicities being myelosuppression and neurotoxicity. Pharmacokinetics (PK) of VBL is primarily driven by ABCB1‐mediated efflux and CYP3A4 metabolism, creating potential for drug–drug interaction. To characterize sources of variability in VBL PK, we developed a physiologically based pharmacokinetic (PBPK) model in Mdr1a/b(−/−) knockout and wild‐type mice by incorporating key drivers of PK, including ABCB1 efflux, CYP3A4 metabolism, and tissue‐specific tubulin binding, and scaled this model to accurately simulate VBL PK in humans and pet dogs. To investigate the capability of the model to capture interindividual variability in clinical data, virtual populations of humans and pet dogs were generated through Monte Carlo simulation of physiologic and biochemical parameters and compared to the clinical PK data. This model provides a foundation for predictive modeling of VBL PK. The base PBPK model can be further improved with supplemental experimental data identifying drug–drug interactions, ABCB1 polymorphisms and expression, and other sources of physiologic or metabolic variability.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Vinblastine pharmacokinetics in mouse, dog, and human in the context of a physiologically based model incorporating tissue‐specific drug binding, transport, and metabolism

Witta

Collins

Ramirez

et al. 2023

Pharmacology Res & Perspec

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“…Reaction kinetics for ITZ hydroxylation to OH‐ITZ in each of the 9 rCYPs were established using the following final reaction conditions: NADPH‐RS (1 mM NADP, 1 mM G6PDH, 5 mM G6P) and 50 nM rCYP (Achanta & Maxwell, 2016) in 100 mM potassium phosphate buffer incubated for 60 min, as established for DLMs. Final ITZ substrate concentrations ranged from 4–32 μM in triplicate.…”

Section: Methodsmentioning

confidence: 99%

Cytochrome P450 reaction phenotyping of itraconazole hydroxylation in the dog

Tonero

Reinhart

2022

Vet Pharm & Therapeutics

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Itraconazole (ITZ) is an important drug in the treatment of superficial and deep mycoses in dogs. Its primary metabolite is hydroxy‐itraconazole, which has antifungal activity similar to the parent compound. The purpose of this study was to identify the cytochrome P450 enzyme (CYP) isoform(s) responsible for ITZ hydroxylation in canine liver. Reaction kinetics for ITZ hydroxylation were determined in a panel of canine recombinant CYPs and dog liver microsomes (DLMs). Findings were confirmed using CYP isoform‐specific inhibitors in rCYPs and DLMs. In rCYP experiments, CYP2D15 and CYP3A12 had highest activity for ITZ hydroxylation. In inhibitor experiments, quinidine and erythromycin inhibited ITZ hydroxylation in CYP2D15 and CYP3A12, respectively, in an isoform‐specific manner. In DLMs, quinidine and erythromycin combined inhibited ITZ hydroxylation more than erythromycin alone but not quinidine alone. However, this may be related to inhibitor potency rather than the contribution of the individual CYP isoforms to the reaction. These findings support a role for CYP2D15 and CYP3A12 in ITZ biotransformation in canine liver.

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“…Vinca alkaloids, such as vinblastine, vinorelbine and vincristine, are anti-mitotic and anti-microtubule alkaloid agents derived from the periwinkle plant Catharanthus roseus [22]. Vinblastine is the first-line anti-neoplastic drug for treatment of Hodgkin's lymphoma, choriocarcinoma and testicular tumors [23] and executes its cytotoxicity on cancer cells by binding to tubulin [24].…”

Section: Introductionmentioning

confidence: 99%

RIP1/RIP3/MLKL-mediated necroptosis contributes to vinblastine-induced myocardial damage

Zhou

Liu

et al. 2020

Mol Cell Biochem

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Vinblastine (VBL) has been considered as a first-line anti-tumor drug for many years. However, vinblastine-caused myocardial damage has been continually reported. The underlying molecular mechanism of the myocardial damage remains unknown. Here, we show that vinblastine induces myocardial damage and necroptosis is involved in the vinblastine-induced myocardial damage both in vitro and in vivo. The results of WST-8 and flow cytometry analysis show that vinblastine causes damage to H9c2 cells, and the results of animal experiments show that vinblastine causes myocardial cell damage. The necrosome components, receptor-interacting protein 1 (RIP1) receptor-interacting protein 3 (RIP3), are significantly increased in vinblastine-treated H9c2 cells, primary neonatal rat ventricular myocytes and rat heart tissues. And the downstream substrate of RIP3, mixed lineage kinase domain like protein (MLKL) was also increased. Pre-treatment with necroptosis inhibitors partially inhibits the necrosome components and MLKL levels and alleviates vinblastine-induced myocardial injury both in vitro and in vivo. This study indicates that necroptosis participated in vinblastine-evoked myocardial cell death partially, which would be a potential target for relieving the chemotherapy-related myocardial damage.

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Reaction phenotyping of vinblastine metabolism in dogs

Cited by 5 publications

References 35 publications

Vinblastine pharmacokinetics in mouse, dog, and human in the context of a physiologically based model incorporating tissue‐specific drug binding, transport, and metabolism

Vinblastine pharmacokinetics in mouse, dog, and human in the context of a physiologically based model incorporating tissue‐specific drug binding, transport, and metabolism

Cytochrome P450 reaction phenotyping of itraconazole hydroxylation in the dog

RIP1/RIP3/MLKL-mediated necroptosis contributes to vinblastine-induced myocardial damage

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