Pharmacokinetic drivers of toxicity for basic molecules: Strategy to lower pKa results in decreased tissue exposure and toxicity for a small molecule Met inhibitor

Diaz, Dolores; Ford, Kevin A.; Hartley, Dylan P.; Harstad, Eric B.; Cain, Gary; Achilles-Poon, Kirsten; Nguyen, Trung Van; Peng, Jianchun; Zheng, Zhong; Merchant, Mark; Sutherlin, Daniel P.; Gaudino, John J.; Kaus, Robert; Lewin-Koh, Sock Cheng; Choo, Edna F.; Liederer, Bianca M.; Dambach, Donna M.

doi:10.1016/j.taap.2012.10.026

Cited by 31 publications

(35 citation statements)

References 26 publications

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“…The overall algorithm to determine semiquantitative and quantitative estimates of K p values (Fig. ) was further tested in a case study to retrospectively predict liver and BM distribution of two small molecule MET kinase inhibitors (#28 and #29), for which structural changes resulted in lower tissue distribution, decreased toxicity, and improved safety margins . The aim was to verify whether Gen #28 had greater tissue distribution in BM and liver compared with Gen #29, as it was expected based on tissue drug measurements.…”

Section: Methodsmentioning

confidence: 99%

“…The distribution of drugs into tissues, that is, tissue accumulation, is a recognized contributor to drug toxicity; however, evaluation of tissue drug partitioning under in vivo condition is not routinely performed in toxicology studies, partly because it is resource‐intensive. This issue can also be approached with physiologically based pharmacokinetics (PK) modeling, where the impacts of dosing regimen on tissue distribution can be predicted from description of its controlling processes, although this could be a data‐intensive approach.…”

Section: Introductionmentioning

confidence: 99%

“…Finally, the utility of the proposed algorithm in drug discovery was also challenged in a case study to predict differential tissue distribution of two small molecule MET kinase inhibitors from their in vivo V d and CL values. Accordingly, Diaz et al . recently reported that minimal structural changes lowering ionization constant (p K a) for one small molecule MET kinase inhibitor compared to another caused significant changes in V d (decreased) and CL (increased), which resulted in lowered tissue distribution and reduced toxicity profiles in mice.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

An Algorithm for Evaluating Potential Tissue Drug Distribution in Toxicology Studies from Readily Available Pharmacokinetic Parameters

Poulin¹,

Dambach²,

Hartley

et al. 2013

Journal of Pharmaceutical Sciences

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An Algorithm for Evaluating Potential Tissue Drug Distribution in Toxicology Studies from Readily Available Pharmacokinetic Parameters

Poulin¹,

Dambach²,

Hartley

et al. 2013

Journal of Pharmaceutical Sciences

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“…In animal experiments, the highly selective c-Met inhibitor GEN-203 and compound 8 may cause liver and bone marrow toxicity in mice [57] and myocardial degeneration in rats [58], respectively. In the clinical trials, severe adverse events, including leukopenia, anemia, and neutropenia, were observed in a phase 1b study of tivantinib (ARQ197) for patients with HCC [59].…”

Section: Side Effects In C-met Targetingmentioning

confidence: 99%

The Therapeutic Targeting of HGF/c-Met Signaling in Hepatocellular Carcinoma: Alternative Approaches

Cheng

et al. 2017

Cancers

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The poor prognosis of hepatocellular carcinoma (HCC), one of the most devastating cancers worldwide, is due to frequent recurrence and metastasis. Among the metastatic factors in the tumor microenvironment, hepatocyte growth factor (HGF) has been well known to play critical roles in tumor progression, including HCC. Therefore, c-Met is now regarded as the most promising therapeutic target for the treatment of HCC. However, there are still concerns about resistance and the side effects of using conventional inhibitors of c-Met, such as tyrosine kinase inhibitors. Recently, many alternative strategies of c-Met targeting have been emerging. These include targeting the downstream effectors of c-Met, such as hydrogen peroxide-inducible clone 5 (Hic-5), to block the reactive oxygen species (ROS)-mediated signaling for HCC progression. Also, inhibition of endosomal regulators, such as PKCε and GGA3, may perturb the c-Met endosomal signaling for HCC cell migration. On the other hand, many herbal antagonists of c-Met-dependent signaling, such as saponin, resveratrol, and LZ-8, were identified. Taken together, it can be anticipated that more effective and safer c-Met targeting strategies for preventing HCC progression can be established in the future.

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“…The pK A governs solubility, volume of distribution and clearance of drug molecules [4][5][6][7][8] and the thermodynamics of metabolic reactions 9 . Drugs usually need to penetrate cell membranes to become active, which they can do efficiently only in the uncharged state 7 . The charge state of a drug depends on its pK A and environment.…”

Section: Introductionmentioning

confidence: 99%

Computing pK_a Values in Different Solvents by Electrostatic Transformation

Rossini

Netz

Knapp

2016

J. Chem. Theory Comput.

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We introduce a method that requires only moderate computational effort to compute pKa values of small molecules in different solvents with an average accuracy of better than 0.7 pH units. With a known pKa value in one solvent, the electrostatic transform method computes the pKa value in any other solvent if the proton solvation energy is known in both considered solvents. To apply the electrostatic transform method to a molecule, the electrostatic solvation energies of the protonated and deprotonated molecular species are computed in the two considered solvents using a dielectric continuum to describe the solvent. This is demonstrated for 30 molecules belonging to 10 different molecular families by considering 77 measured pKa values in 4 different solvents: water, acetonitrile, dimethyl sulfoxide, and methanol. The electrostatic transform method can be applied to any other solvent if the proton solvation energy is known. It is exclusively based on physicochemical principles, not using any empirical fetch factors or explicit solvent molecules, to obtain agreement with measured pKa values and is therefore ready to be generalized to other solute molecules and solvents. From the computed pKa values, we obtained relative proton solvation energies, which agree very well with the proton solvation energies computed recently by ab initio methods, and used these energies in the present study.

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Pharmacokinetic drivers of toxicity for basic molecules: Strategy to lower pKa results in decreased tissue exposure and toxicity for a small molecule Met inhibitor

Cited by 31 publications

References 26 publications

An Algorithm for Evaluating Potential Tissue Drug Distribution in Toxicology Studies from Readily Available Pharmacokinetic Parameters

An Algorithm for Evaluating Potential Tissue Drug Distribution in Toxicology Studies from Readily Available Pharmacokinetic Parameters

The Therapeutic Targeting of HGF/c-Met Signaling in Hepatocellular Carcinoma: Alternative Approaches

Computing pK_a Values in Different Solvents by Electrostatic Transformation

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Pharmacokinetic drivers of toxicity for basic molecules: Strategy to lower pKa results in decreased tissue exposure and toxicity for a small molecule Met inhibitor

Cited by 31 publications

References 26 publications

An Algorithm for Evaluating Potential Tissue Drug Distribution in Toxicology Studies from Readily Available Pharmacokinetic Parameters

An Algorithm for Evaluating Potential Tissue Drug Distribution in Toxicology Studies from Readily Available Pharmacokinetic Parameters

The Therapeutic Targeting of HGF/c-Met Signaling in Hepatocellular Carcinoma: Alternative Approaches

Computing pKa Values in Different Solvents by Electrostatic Transformation

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Product

Resources

About

Computing pK_a Values in Different Solvents by Electrostatic Transformation