Role of the OATP Transporter Family and a Benzbromarone-SensitiveEfflux Transporter in the Hepatocellular Disposition of Vincristine

Nicolaï, Johan; Thevelin, Louise; Qi, Bing; Stieger, Bruno; Chanteux, Hugues; Augustijns, Patrick; Annaert, Pieter

doi:10.1007/s11095-017-2241-0

Cited by 10 publications

(11 citation statements)

References 44 publications

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“…Thus, it seems that biliary efflux via P‐gp may not be the critical factor in defining vincristine hepatic clearance. Studies utilizing suspended cryopreserved human hepatocytes also indicate that the rate‐limiting factor is not efflux via P‐gp, which is consistent with the conclusion reached based on the sensitivity analyses but suggests a possible role of BL organic anion transporter proteins in rate‐limiting uptake into hepatocytes.…”

Section: Discussionsupporting

confidence: 83%

“…Although vincristine is well known as a substrate of P‐gp, kinetic parameters of its efflux have not previously been reported. Kinetic studies of P‐gp efflux are often performed in vitro using inside‐out membrane vesicle systems overexpressing MDR1; however, it is difficult to achieve adequate intravesicular concentrations of lipophilic compounds such as vincristine for evaluation . The permeability (P app ) of vincristine (10 μM) across MDCKII‐MDR1 monolayers is sevenfold greater in the BL to AP direction (157 nm/s) than in the AP to BL direction (22 nm/s), consistent with AP efflux.…”

Section: Resultsmentioning

confidence: 97%

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Physiologically Based Pharmacokinetic Models for Adults and Children Reveal a Role of Intracellular Tubulin Binding in Vincristine Disposition

Lee

Zane

Veal

et al. 2019

CPT Pharmacom & Syst Pharma

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Vincristine is a cytotoxic chemotherapeutic agent used as first‐line therapy for pediatric acute lymphocytic leukemia. It is cleared by hepatic oxidative metabolism by CYP3A4 and CYP3A5 and via hepatic (biliary) efflux mediated by P‐glycoprotein (P‐gp) transporter. Bottom‐up physiologically based pharmacokinetic (PBPK) models were developed to predict vincristine disposition in pediatric and adult populations. The models incorporated physicochemical properties, metabolism by CYP3A4/5, efflux by P‐gp, and intracellular binding to β‐tubulin. The adult and pediatric PBPK models predicted pharmacokinetics (PK) within twofold of the observed PK parameters (area under the curve, terminal half‐life, volume of distribution, and clearance). Simulating a higher hypothetical (4.9‐fold) pediatric expression of β‐tubulin relative to adult improved predictions of vincristine PKs. To our knowledge, this is the first time that intracellular binding has been incorporated into a pediatric PBPK model. Utilizing this PBPK modeling approach, safe and effective doses of vincristine could be predicted.

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Section: Discussionsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 97%

Physiologically Based Pharmacokinetic Models for Adults and Children Reveal a Role of Intracellular Tubulin Binding in Vincristine Disposition

Lee

Zane

Veal

et al. 2019

CPT Pharmacom & Syst Pharma

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“…49 MRP2 can also transport vincristine in cells but the significance of this transport in vivo is not known. 50 Similarly, vincristine has been shown to be transported by OATP1B1 and OATP1B3 in vitro, 51,52 although their contribution to vincristine disposition or neurotoxicity are not characterized.…”

Section: Platinsmentioning

confidence: 99%

Role for Drug Transporters in Chemotherapy‐Induced Peripheral Neuropathy

Stage

Sparreboom

et al. 2020

Clinical Translational Sci

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Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting toxicity to widely used chemotherapeutics. Although the exact molecular mechanism of chemotherapy-induced peripheral neuropathy remains elusive, there is consensus that it is caused by damage to the peripheral nervous system leading to sensory symptoms. Recently developed methodologies have provided evidence of expression of drug transporters in the peripheral nervous system. In this literature review, we explore the role for drug transporters in CIPN. First, we assessed the transport of chemotherapeutics that cause CIPN (taxanes, platins, vincristine, bortezomib, epothilones, and thalidomide). Second, we cross-referenced the transporters implicated in genetic or functional studies with CIPN with their expression in the peripheral nervous system. Several drug transporters are involved in the transport of chemotherapeutics that cause peripheral neuropathy and particularly efflux transporters, such as ABCB1 and ABCC1, are expressed in the peripheral nervous system. Previous literature has linked genetic variants in efflux transporters to higher risk of peripheral neuropathy with the taxanes paclitaxel and docetaxel and the vinca alkaloid vincristine. We propose that this might be due to accumulation of the chemotherapeutics in the peripheral nervous system due to reduced neuronal efflux capacity. Thus, concomitant administration of efflux transporter inhibitors may lead to higher risk of adverse events of drugs that cause CIPN. This might prove valuable in drug development where screening new drugs for neurotoxicity might also require drug transporter consideration. There are ongoing efforts targeting drug transporters in the peripheral nervous system to reduce intraneuronal concentrations of chemotherapeutics that cause CIPN, which might ultimately protect against this dose-limiting adverse event.

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“…Among these drugs, only vincristine and vinorelbine have been assayed in the treatment of patients with HB [117]. OATP transporters have been involved in the uptake of vincristine [118] and the expression of both SLCO1B1 and SLCO1B3 have been found lower in HB than in adjacent non-tumor tissue [10]. SLC22A3 expression has been associated with the sensitivity to vincristine in kidney carcinoma cell lines [119], but no changes in the expression of this gene in HB have been found [10].…”

Section: Mechanisms Of Hb Resistance To Vinca Alkaloidsmentioning

confidence: 99%

Mechanisms of Anticancer Drug Resistance in Hepatoblastoma

Marin

Cives-Losada

Asensio

et al. 2019

Cancers

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The most frequent liver tumor in children is hepatoblastoma (HB), which derives from embryonic parenchymal liver cells or hepatoblasts. Hepatocellular carcinoma (HCC), which rarely affects young people, causes one fourth of deaths due to cancer in adults. In contrast, HB usually has better prognosis, but this is still poor in 20% of cases. Although more responsive to chemotherapy than HCC, the failure of pharmacological treatment used before and/or after surgical resection is an important limitation in the management of patients with HB. To advance in the implementation of personalized medicine it is important to select the best combination among available anti-HB drugs, such as platinum derivatives, anthracyclines, etoposide, tyrosine-kinase inhibitors, Vinca alkaloids, 5-fluorouracil, monoclonal antibodies, irinotecan and nitrogen mustards. This requires predicting the sensitivity to these drugs of each tumor at each time because, it should be kept in mind, that cancer chemoresistance is a dynamic process of Darwinian nature. For this goal it is necessary to improve our understanding of the mechanisms of chemoresistance involved in the refractoriness of HB against the pharmacological challenge and how they evolve during treatment. In this review we have summarized the current knowledge on the multifactorial and complex factors responsible for the lack of response of HB to chemotherapy.

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Role of the OATP Transporter Family and a Benzbromarone-SensitiveEfflux Transporter in the Hepatocellular Disposition of Vincristine

Abstract: Our findings show the involvement of OATP transporters in the disposition of vincristine in rat and human hepatocytes. However, in both species, hepatic uptake is overshadowed by a benzbromarone-sensitive efflux mechanism, possibly MRP3.

Cited by 10 publications

References 44 publications

Physiologically Based Pharmacokinetic Models for Adults and Children Reveal a Role of Intracellular Tubulin Binding in Vincristine Disposition

Physiologically Based Pharmacokinetic Models for Adults and Children Reveal a Role of Intracellular Tubulin Binding in Vincristine Disposition

Role for Drug Transporters in Chemotherapy‐Induced Peripheral Neuropathy

Mechanisms of Anticancer Drug Resistance in Hepatoblastoma

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