Temperature dependence and thermodynamics of partitioning of clofazimine analogues in the n-octanol/water system

Quigley, John M.; Fahelelbom, Khairi M. S.; Timoney, R. F.; Corrigan, Owen I.

doi:10.1016/0378-5173(90)90247-2

Cited by 16 publications

(14 citation statements)

References 30 publications

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“…The molecular weight of clofazimine is 473 g/mol, and the log P octanol:water value used was 7.66 (ChemIDplus database; U.S. National Library of Medicine, Bethesda, MD, https://chem.nlm.nih.gov/chemidplus/). The compound type was entered as a monoprotic base with an acid dissociation constant pK a value of 8.51 (Quigley et al, 1990). The blood-to-plasma ratio was entered as 0.5 (minimally distributed into blood; internal data), and the fu p was entered as 0.001 (http:// www.resisttb.org/wp-content/uploads/2013/08/Global-Alliance-Clinical-Workwith-Clofazimine.pdf).…”

Section: Downloaded Frommentioning

confidence: 99%

Evaluation of Clinical Drug Interaction Potential of Clofazimine Using Static and Dynamic Modeling Approaches

Sangana

Chun

et al. 2017

Drug Metab Dispos

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The 2016 World Health Organization treatment recommendations for drug-resistant tuberculosis (DR-TB) positioned clofazimine as a core second-line drug. Being identified as a cytochrome P450 (P450) inhibitor in vitro, a P450-mediated drug interaction may be likely when clofazimine is coadministered with substrates of these enzymes. The P450-mediated drug interaction potential of clofazimine was evaluated using both static [estimation of the and area under the plasma concentration-time curve ratio (AUCR) values] and dynamic [physiologically based pharmacokinetics (PBPK)] modeling approaches. For static and dynamic predictions, midazolam, repaglinide, and desipramine were used as probe substrates for CYP3A4/5, CYP2C8, and CYP2D6, respectively. The AUCR static model estimations for clofazimine with the substrates midazolam, repaglinide, and desipramine were 5.59, 1.34, and 1.69, respectively. The fold increases in the area under the curve (AUC) predicted for midazolam, repaglinide, and desipramine with clofazimine (based on PBPK modeling) were 2.69, 1.60, and 1.47, respectively. Clofazimine was predicted to be a moderate-to-strong CYP3A4/5 inhibitor and weak CYP2C8 and CYP2D6 inhibitor based on the calculated AUCR by static and PBPK modeling. Additionally, for selected antiretroviral, antitubercular, antihypertensive, antidiabetic, antileprotics, and antihyperlipidemic CYP3A4/5 substrate drugs, approximately 2- to 6-fold increases in the AUC were predicted with static modeling when coadministered with 100 mg of clofazimine. Therefore, the possibility of an increase in the AUC of CYP3A4/5 substrates when coadministered with clofazimine cannot be ignored.

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Section: Downloaded Frommentioning

confidence: 99%

Evaluation of Clinical Drug Interaction Potential of Clofazimine Using Static and Dynamic Modeling Approaches

Sangana

Chun

et al. 2017

Drug Metab Dispos

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“…In lysosomes, CFZ accumulates as CLDIs, which mostly contain hydrochloride salts of the weak base (CFZ-HCl). Thus, using predetermined physicochemical properties of the free base as well as the salt form of the drug (apparent p K a = 6.08 (28), and octanol/water partition coefficient logP (logKow = 7.66 (26, 27))) as input in the Virtual Cell model, we calculated the time-dependent subcellular distribution of both neutral and ionized molecular species as a function of an extracellular total drug concentration of 10 μM (concentrations in all subcellular compartments are linearly related to the extracellular concentration). We set the extracellular volume to a high value (Table S1), so that the extracellular drug concentrations would remain nearly constant, without being affected by cellular drug uptake.…”

Section: Methodsmentioning

confidence: 99%

“…It exhibits extensive bioaccumulation following oral administration, in both humans and animal models(23–25). Because CFZ is both highly lipophilic (LogP=7.66) (26, 27) and contains an ionizable amine group (apparent p K a =6.08)(28), it is poised to accumulates in adipose tissue, intracellular membranes, and acidic organelles such as lysosomes. In both human and animal models it has been shown that, following prolonged oral dosing, CFZ forms insoluble Crystal-Like Drug Inclusions (CLDIs) within macrophage lysosomes(15).…”

Section: Introductionmentioning

confidence: 99%

An Expandable Mechanopharmaceutical Device (1): Measuring the Cargo Capacity of Macrophages in a Living Organism

et al. 2018

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Purpose: Clofazimine (CFZ) is an FDA-approved, poorly soluble small molecule drug that precipitates as crystal-like drug inclusions (CLDIs) which accumulate in acidic cytoplasmic organelles of macrophages. In this study, we considered CLDIs as an expandable mechanopharmaceutical device, to study how macrophages respond to an increasingly massive load of endophagolysosomal cargo. Methods: First, we experimentally tested how the accumulation of CFZ in CLDIs impacted different immune cell subpopulations of different organs. Second, to further investigate the mechanism of CLDI formation, we asked whether specific accumulation of CFZ hydrochloride crystals in lysosomes could be explained as a passive, thermodynamic equilibrium phenomenon. A cellular pharmacokinetic model was constructed, simulating CFZ accumulation driven by pH-dependent ion trapping of the protonated drug in the acidic lysosomes, followed by the precipitation of CFZ hydrochloride salt via a common ion effect caused by high chloride concentrations. Results: While lower loads of CFZ were mostly accommodated in lung macrophages, increased CFZ loading was accompanied by organ-specific changes in macrophage numbers, size and intracellular membrane architecture, maximizing the cargo storage capabilities. With increasing loads, the total cargo mass and concentrations of CFZ in different organs diverged, while that of individual macrophages converged. The simulation results support the notion that the proton and chloride ion concentrations of macrophage lysosomes are sufficient to drive the massive, cell type-selective accumulation and growth of CFZ hydrochloride biocrystals. Conclusion: CLDIs effectively function as an expandable mechanopharmaceutical device, revealing the coordinated response of the macrophage population to an increasingly massive, whole-organism endophagolysosomal cargo load.

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“…CFZ is a weakly basic drug, with a pKa of 8.511 [23]. In its free base form (CFZB), the API is practically insoluble in neutral, aqueous media with solubility reported to be < 0.01 mg/L [24].…”

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confidence: 99%

Overcoming the Common Ion Effect for Weakly Basic Drugs: Inhibiting the Crystallization of Clofazimine Hydrochloride in Simulated Gastrointestinal Media

Bannigan

Verma

Hudson

2019

Crystal Growth & Design

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Bile salts, phospholipids, and digestive proteins are amphipathic compounds found naturally in the human gastrointestinal system. Therefore, it is important to consider their effects on the crystallization kinetics and solution behaviour of drugs intended for oral delivery. Supersaturating drug delivery systems that employ high energy solid forms and polymeric additives are often hailed as the gold standard for increasing drug concentration in the gastrointestinal system. However, the effects of amphiphilic compounds present in the gastrointestinal system on the crystallization behaviour of these systems are often overlooked. In this study, the effects of bile salts, phospholipids, mixtures of phospholipid and bile salts as well as digestive proteins on the crystallization kinetics of the antimicrobial agent clofazimine (CFZ) were evaluated. The crystallization inhibitory properties of these gastrointestinal amphiphiles were compared with commonly used synthetic polymers, and several of these amphipathic gastrointestinal compounds showed promise as crystallization inhibitors of clofazimine hydrochloride during induction time experiments. The best crystallization inhibitors from this induction time screening were then compared as solid physical mixtures in modified fasted state simulated gastric fluid (m-FaSSGF). Here it was found that heterogeneous nucleation of CFZ hydrochloride onto the dissolving surface of CFZ solid forms prevented these additives from inhibiting crystallization in this biorelevant media. This heterogeneous nucleation of CFZ hydrochloride was monitored in real time, using optical microscopic techniques.

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Temperature dependence and thermodynamics of partitioning of clofazimine analogues in the n-octanol/water system

Cited by 16 publications

References 30 publications

Evaluation of Clinical Drug Interaction Potential of Clofazimine Using Static and Dynamic Modeling Approaches

Evaluation of Clinical Drug Interaction Potential of Clofazimine Using Static and Dynamic Modeling Approaches

An Expandable Mechanopharmaceutical Device (1): Measuring the Cargo Capacity of Macrophages in a Living Organism

Overcoming the Common Ion Effect for Weakly Basic Drugs: Inhibiting the Crystallization of Clofazimine Hydrochloride in Simulated Gastrointestinal Media

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