Physicochemical Profiling in Drug Research and Development

Takács‐Novák, Krisztina

doi:10.5599/obp.7.1

Cited by 3 publications

(3 citation statements)

References 79 publications

(118 reference statements)

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“…A similar P eff,man value was estimated for the analog casearin X (16.4 × 10 −4 cm/s). Casearin X showed an appar- ent permeability of 66.9 × 10 −6 cm/s in Caco-2 cells, with an efflux ratio of 0.1, which suggests that active transport contributes to cell accumulation [21][22][23]. Up to now, there has been no information on the role of drug transporters in the oral bioavailability of casg F and cas B.…”

Section: Resultsmentioning

confidence: 98%

“…1S , Supporting Information). The chromatographic approach for log P determination is accurate for log P values within 0 – 6 21 . The moderate lipophilicity (2.0 < log P < 4.0) indicates that cas B and casg F have high cell permeability.…”

Section: Resultsmentioning

confidence: 99%

“…The log P values assessed by the chromatographic method were 3.8 and 4.0 for casg F and cas B, respectively, and were similar to predicted values (Table1, Fig.1S, Supporting Information). The chromatographic approach for log P determination is accurate for log P values within 0 -6[21]. The moderate lipophilicity (2.0 < log P < 4.0) indicate that cas B and casg F have high cell permeability.…”

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confidence: 96%

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Metabolism Characterization and Chemical and Plasma Stability of Casearin B and Caseargrewiin F

et al. 2023

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Oral preparations of Casearia sylvestris (guacatonga) are used as antacid, analgesic, anti-inflammatory and antiulcerogenic activities. The clerodane diterpenes casearin B (cas B) and caseargrewiin F (casg F) are major active compounds in vitro and in vivo. The oral bioavailability and metabolism of cas B and casg F were not previously investigated. We aimed to assess the stability of cas B and casg F in physiological conditions and their metabolism in human liver microsomes (HLM). The compounds were identified by UHPLC-QTOF-MS/MS and quantified by validated LC-MS methods. The stability of cas B and casg F in physiological conditions was assessed in vitro. Both diterpenes showed a fast degradation (p < 0.05) in simulated gastric fluid. Their metabolism is not mediated by cytochrome P-450 enzymes, but the depletion was inhibited by the esterase inhibitor NaF. Both diterpenes and their dialdehydes showed log P in the range of 3.6 to 4.0, suggesting high permeability. Metabolism kinetic data were fitted to the Michaelis-Menten profile with KM values of 61.4 μM and 66.4 μM and Vmax values of 327 and 648 nmol/min/mg of protein for cas B and casg F, respectively. Metabolism parameters in HLM were extrapolated to predict human hepatic clearance and suggest that casg F and cas B have a high hepatic extraction ratio. In conclusion, our data suggest that casg F and cas B present low oral bioavailability due to extensive gastric degradation and high hepatic extraction.

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confidence: 98%

Section: Resultsmentioning

confidence: 99%

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confidence: 96%

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Metabolism Characterization and Chemical and Plasma Stability of Casearin B and Caseargrewiin F

et al. 2023

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Log D_7.4 and plasma protein binding of synthetic cannabinoid receptor agonists and a comparison of experimental and predicted lipophilicity

Brandon,

Baginski,

Peet

et al. 2023

Drug Testing and Analysis

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The emergence of new synthetic cannabinoid receptor agonists (SCRAs) onto the illicit drugs market continues to cause harm, and the overall availability of physicochemical and pharmacokinetic data for new psychoactive substances is lacking. The lipophilicity of 23 SCRAs and the plasma protein binding (PPB) of 11 SCRAs was determined. Lipophilicity was determined using a validated chromatographic hydrophobicity index (CHI) log D method; tested SCRAs showed moderate to high lipophilicity, with experimental log D7.4 ranging from 2.48 (AB‐FUBINACA) to 4.95 (4F‐ABUTINACA). These results were also compared to in silico predictions generated using seven commercially available software packages and online tools (Canvas; ChemDraw; Gastroplus; MoKa; PreADMET; SwissADME; and XlogP). Licenced, dedicated software packages provided more accurate lipophilicity predictions than those which were free or had prediction as a secondary function; however, the latter still provided competitive estimates in most cases. PPB of tested SCRAs, as determined by equilibrium dialysis, was in the upper range of the lipophilicity scale, ranging from 90.8% (ADB‐BUTINACA) to 99.9% (BZO‐HEXOXIZID). The high PPB of these drugs may contribute to reduced rate of clearance and extended durations of pharmacological effects compared to lesser‐bound SCRAs. The presented data improve understanding of the behaviour of these drugs in the body. Ultimately, similar data and predictions may be used in the prediction of the structure and properties of drugs yet to emerge on the illicit market.

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Prediction of pH-Dependent Hydrophobic Profiles of Small Molecules from Miertus–Scrocco–Tomasi Continuum Solvation Calculations

et al. 2017

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Hydrophobicity is a key physicochemical descriptor used to understand the biological profile of (bio)organic compounds as well as a broad variety of biochemical, pharmacological, and toxicological processes. This property is estimated from the partition coefficient between aqueous and nonaqueous environments for neutral compounds (P) and corrected for the pH-dependence of ionizable compounds as the distribution coefficient (D). Here, we have extended the parametrization of the Miertus-Scrocco-Tomasi continuum solvation model in n-octanol to nitrogen-containing heterocyclic compounds, as they are present in many biologically relevant molecules (e.g., purines and pyrimidines bases, amino acids, and drugs), to obtain accurate log P values for these molecules. This refinement also includes solvation calculations for ionic species in n-octanol with the aim of reproducing the experimental partition of ionic compounds (P). Finally, the suitability of different formalisms to estimate the distribution coefficient for a wide range of pH values has been examined for a set of small acidic and basic compounds. The results indicate that in general the simple pH-dependence model of the ionizable compound in water suffices to predict the partitioning at or around physiological pH. However, at extreme pH values, where ionic species are predominant, more elaborate models provide a better prediction of the n-octanol/water distribution coefficient, especially for amino acid analogues. Finally, the results also show that these formalisms are better suited to reproduce the experimental pH-dependent distribution curves of log D for both acidic and basic compounds as well as for amino acid analogues.

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Physicochemical Profiling in Drug Research and Development

Cited by 3 publications

References 79 publications

Metabolism Characterization and Chemical and Plasma Stability of Casearin B and Caseargrewiin F

Metabolism Characterization and Chemical and Plasma Stability of Casearin B and Caseargrewiin F

Log D_7.4 and plasma protein binding of synthetic cannabinoid receptor agonists and a comparison of experimental and predicted lipophilicity

Prediction of pH-Dependent Hydrophobic Profiles of Small Molecules from Miertus–Scrocco–Tomasi Continuum Solvation Calculations

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Physicochemical Profiling in Drug Research and Development

Cited by 3 publications

References 79 publications

Metabolism Characterization and Chemical and Plasma Stability of Casearin B and Caseargrewiin F

Metabolism Characterization and Chemical and Plasma Stability of Casearin B and Caseargrewiin F

Log D7.4 and plasma protein binding of synthetic cannabinoid receptor agonists and a comparison of experimental and predicted lipophilicity

Prediction of pH-Dependent Hydrophobic Profiles of Small Molecules from Miertus–Scrocco–Tomasi Continuum Solvation Calculations

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Product

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Log D_7.4 and plasma protein binding of synthetic cannabinoid receptor agonists and a comparison of experimental and predicted lipophilicity