Plasma protein binding: From discovery to development

Bohnert, Tonika; Gan, Liang‐Shang

doi:10.1002/jps.23614

Cited by 293 publications

(287 citation statements)

References 154 publications

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“…pf pf pf pf 1 r (6) where pf u,obs,i and pf u,calc,i are the observed and calculated by the model values of pf u for the i -th drug, pf u,obs,mean -the mean pf u value for the training set. Fisher's statistics of the models was also calculated.…”

Section: Development Of Qspkr Modelsmentioning

confidence: 99%

“…Drugs that are excreted solely by glomerular filtration have low CL, restricted by PPB, while drugs, substrates of active secretion transporters, are eliminated with high CL, independent of PPB. Consequently, PPB may affect considerably t 1 The complex effects of PPB on PK and PD are discussed in several reviews and books (3)(4)(5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

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Quantitative Structure – Pharmacokinetics Relationships for Plasma Protein Binding of Basic Drugs

Zhivkova

2017

J Pharm Pharm Sci

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Purpose. Binding of drugs to plasma proteins is a common physiological occurrence which may have a profound effect on both pharmacokinetics and pharmacodynamics. The early prediction of plasma protein binding (PPB) of new drug candidates is an important step in drug development process. The present study is focused on the development of quantitative structure -pharmacokinetics relationship (QSPkR) for the negative logarithm of the free fraction of the drug in plasma (pf u ) of basic drugs. Methods. A dataset includes 220 basic drugs, which chemical structures are encoded by 176 descriptors. Genetic algorithm, stepwise regression and multiple linear regression are used for variable selection and model development. Predictive ability of the model is assessed by internal and external validation. Results. A simple, significant, interpretable and predictive QSPkR model is constructed for pf u of basic drugs. It is able to predict 59% of the drugs from an external validation set within the 2-fold error of the experimental values with squared correlation coefficient of prediction 0.532, geometric mean fold error (GMFE) 1.94 and mean absolute error (MAE) 0.17. Conclusions. PPB of basic drugs is favored by the lipophilicity, the presence of aromatic C-atoms (either non-substituted, or involved in bridged aromatic systems) and molecular volume. The fraction ionized as a base f B and the presence of quaternary Catoms contribute negatively to PPB. A short checklist of criteria for high PPB is defined, and an empirical rule for distinguishing between low, high and very high plasma protein binders is proposed based. This rule allows correct classification of 69% of the very high binders, 71% of the high binders and 91% of the low binders in plasma.

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Section: Development Of Qspkr Modelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantitative Structure – Pharmacokinetics Relationships for Plasma Protein Binding of Basic Drugs

Zhivkova

2017

J Pharm Pharm Sci

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“…Although PZQ1 has been employed for decades, few pharmacokinetic studies have been performed with humans (26), although a study carried out with healthy volunteers demonstrated that absorption of PZQ1 is relatively fast (time to maximum concentration of drug in serum [T max ], 2.0 to 2.6 h) and nearly complete (Ͼ80%), which demonstrates an extensive first-pass effect (35). The systemic bioavailability of PZQ1 is low and varies considerably among individuals.…”

Section: Pzq Pharmacokineticsmentioning

confidence: 99%

“…Nonetheless, metabolites of PZQ1 are less active than the parent drug (47). Although the enzymes that metabolize PZQ1 are not fully known, PZQ1 is primarily metabolized by CYP 3A and to a lesser extent by CYP 2D6 (35). Several studies have been performed to clarify the metabolic profile of PZQ1, as well as the enzymes involved and the identities of the phase II metabolites (48)(49)(50)(51)(52)(53).…”

Section: Insights Into Metabolism Of Pzqmentioning

confidence: 99%

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Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

Vale

Gouveia

Rinaldi

et al. 2017

Antimicrob Agents Chemother

270

244

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Schistosomiasis, a major neglected tropical disease, affects more than 250 million people worldwide. Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. PZQ is the drug of choice for the treatment of schistosomiasis; it is effective against all major forms of schistosomiasis, although it is less active against juvenile than mature parasites. A pyrazino-isoquinoline derivative, PZQ is not considered to be toxic and generally causes few or transient, mild side effects. Increasingly, mass drug administration targeting populations in sub-Saharan Africa where schistosomiasis is endemic has led to the appearance of reduced efficacy of PZQ, which portends the selection of drugresistant forms of these pathogens. The synthesis of improved derivatives of PZQ is attracting attention, e.g., in the (i) synthesis of drug analogues, (ii) rational design of pharmacophores, and (iii) discovery of new compounds from large-scale screening programs. This article reviews reports from the 1970s to the present on the metabolism and mechanism of action of PZQ and its derivatives against schistosomes.

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Species Differences and Impact of Disease State on BBB

Nicolas

2015

Blood‐Brain Barrier in Drug Discovery

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Plasma protein binding: From discovery to development

Cited by 293 publications

References 154 publications

Quantitative Structure – Pharmacokinetics Relationships for Plasma Protein Binding of Basic Drugs

Quantitative Structure – Pharmacokinetics Relationships for Plasma Protein Binding of Basic Drugs

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

Species Differences and Impact of Disease State on BBB

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