Absorption, Distribution, and Excretion of DJ-927, a Novel Orally Effective Taxane, in Mice, Dogs, and Monkeys

Ono, Chiho; Takao, Atsushi; Atsumi, Ryo

doi:10.1248/bpb.27.345

Cited by 22 publications

(11 citation statements)

References 24 publications

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“…In detailed PK studies, 146 was rapidly absorbed in mice, dogs, and monkeys following oral administration, with plasma elimination biphasic in nature and dependent on species. 305 In dogs, the elimination half-life was longer than that in mice or monkeys, and in the mouse, radioactivity was widely distributed to all tissues with the exception of the CNS. The oral bioavailability of 146 was 107%, 47%, and 63% in mice, dogs, and monkeys, respectively.…”

Section: Chemical Research In Toxicologymentioning

confidence: 97%

Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space

Meanwell

2016

Chem. Res. Toxicol.

173

133

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Drug discovery and development is a complex and lengthy enterprise that suffers from high rates of candidate attrition at all stages of the process. The physical, biological, and toxicological properties of a drug candidate are inextricably linked to its structure, and once a molecule has been synthesized, all subsequent studies along the development path are focused only on assessing and understanding its properties in greater detail. Unfortunately, a full prediction of the biological properties of a molecule from an analysis of its 2- or 3-dimensional structure is currently beyond our expertise. This backdrop mandates that considerable care be taken at the design stage if a molecule is to be successful in testing a mechanistic concept underlying a disease process and to progress into late stage clinical trials and, ultimately, marketing approval. While there are multiple potential causes of candidate attrition, an introspective analysis of drug design practices over the past decade has focused attention on the perception that contemporary molecules are unnecessarily obese, burdened by high molecular weight and excessive lipophilicity. This practice is believed to have its roots in the singular pursuit of enhancing potency during lead optimization rather than adopting a more holistic approach to drug design that gives broader consideration to how structural features affect developability properties. In an effort to provide the medicinal chemistry community with practical guideposts to enhancing compound quality in the drug design phase and which can readily be applied, a series of efficiency indices have been proposed that attempt to define aspects of compound quality in the context of a series of physicochemical parameters. Of these metrics, lipophilic ligand efficiency (LLE or LipE), which provides an index of the dependence of the potency of a molecule on its intrinsic lipophilicity, has been characterized as the most robust metric that has potential for broad-based application. In this review, after describing the background literature behind the derivation of efficiency metrics and approaches to assessing compound aesthetics, synopses of some recent practical application in lead optimization campaigns are presented. However, molecules that fall into space beyond that associated with traditional drug-like properties are an important part of the current and future landscape, exemplified by the summary of direct acting hepatitis C virus NS3 and NS5A inhibitors that have transformed clinical therapy for this chronic disease. While drug development in nontraditional drug-like space is more challenging and the rules for compound quality will be different with much still to be understood, careful and disciplined drug design practices will be an essential element of success.

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Section: Chemical Research In Toxicologymentioning

confidence: 97%

Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space

Meanwell

2016

Chem. Res. Toxicol.

173

133

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“…These include taxane analogs DJ-927 (phase I/Il)[57]–[59] and ortataxel (phase II)[60],[61], as well as BMS-184476 (phase II)[62]–[64] and RPR 109881A (phase I)[65]–[67], which were purported to have a broad spectrum of activity both in sensitive and resistant tumor cell lines. Nab-paclitaxel is a novel clinical entity incorporating paclitaxel into an albumin nanoparticle, leading to increased intratumoral concentration and showing with superior response rate, longer time to tumor progression, and prolonged survival as second-line therapy in patients with gynecologic cancers[68],[69].…”

Section: Cancer Nanomedicine For Overcoming Drug Efflux-mediated Resimentioning

confidence: 99%

Overcoming drug efflux-based multidrug resistance in cancer with nanotechnology

Xue¹,

Liang²

2012

Chin J Cancer

144

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Multidrug resistance (MDR), which significantly decreases the efficacy of anticancer drugs and causes tumor recurrence, has been a major challenge in clinical cancer treatment with chemotherapeutic drugs for decades. Several mechanisms of overcoming drug resistance have been postulated. Well known P-glycoprotein (P-gp) and other drug efflux transporters are considered to be critical in pumping anticancer drugs out of cells and causing chemotherapy failure. Innovative theranostic (therapeutic and diagnostic) strategies with nanoparticles are rapidly evolving and are anticipated to offer opportunities to overcome these limits. In this review, we discuss the mechanisms of drug efflux-mediated resistance and the application of multiple nanoparticle-based platforms to overcome chemoresistance and improve therapeutic outcome.

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“…Two taxane analogs, DJ-927 (Phase I) [57,58] and ortataxel (Phase II) [59,60], designed to overcome drug resistance, have been evaluated in clinical trials. Other novel taxane analogs, such as BMS-184476 (Phase I) [61,62] and RPR 109881A (Phase II) [63,64], were also claimed to have a broad spectrum of activity both in sensitive and resistant tumor cell lines.…”

Section: Seven Strategies To Overcome Mdrmentioning

confidence: 99%

Nanomedicinal Strategies to Treat Multidrug-Resistant Tumors: Current Progress

2010

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Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. Pglycoprotein is an important and the best-known membrane transporter involved in MDR. Several strategies have been used to address MDR, especially P-glycoprotein-mediated drug resistance in tumors. However, clinical success has been limited, largely due to issues regarding lack of efficacy and/or safety. Nanoparticles have shown the ability to target tumors based on their unique physical and biological properties. To date, nanoparticles have been investigated primarily to address P-glycoprotein and the observed improved anticancer efficacy suggests that nanomedicinal strategies provide a new opportunity to overcome MDR. This article focuses on nanotechnology-based formulations and current nanomedicine approaches to address MDR in tumors and discusses the proposed mechanisms of action.

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Absorption, Distribution, and Excretion of DJ-927, a Novel Orally Effective Taxane, in Mice, Dogs, and Monkeys

Cited by 22 publications

References 24 publications

Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space

Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space

Overcoming drug efflux-based multidrug resistance in cancer with nanotechnology

Nanomedicinal Strategies to Treat Multidrug-Resistant Tumors: Current Progress

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