Pharmacokinetic Principles

Brown, David F.M.; Tomlin, Mark

doi:10.1007/978-1-84996-146-2_2

Cited by 4 publications

(6 citation statements)

References 19 publications

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“…The α and β phases are primarily attributed to the drug distribution from the central compartment (circulation) and elimination by metabolism and excretion, respectively. 58 Based on the curcumin plasma concentration (ID%; Figure 9 ) and PK ( Table 4 ), the crucial part of the circulation kinetics of curcumin encompasses the first 4 h, where most of the curcumin was eliminated from the circulation and during which time the initial half-life is defined. In contrast, mPEG 5kDa - b -p(HPMA-Bz) 17.1kDa micelles exhibited a prolonged circulation time with a t 1/2 of 42 h ( Table 4 ).…”

Section: Resultsmentioning

confidence: 99%

“…The PK profile of curcumin in plasma demonstrated that the initial ( t 1/2α ) and terminal elimination phase ( t 1/2β ) were 6.7 min and 2.5 h, respectively. The α and β phases are primarily attributed to the drug distribution from the central compartment (circulation) and elimination by metabolism and excretion, respectively . Based on the curcumin plasma concentration (ID%; Figure ) and PK (Table ), the crucial part of the circulation kinetics of curcumin encompasses the first 4 h, where most of the curcumin was eliminated from the circulation and during which time the initial half-life is defined.…”

Section: Resultsmentioning

confidence: 99%

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In Vitro and In Vivo Studies on HPMA-Based Polymeric Micelles Loaded with Curcumin

et al. 2021

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Curcumin-loaded polymeric micelles composed of poly(ethylene glycol)- b -poly( N -2-benzoyloxypropyl methacrylamide) (mPEG- b -p(HPMA-Bz)) were prepared to solubilize and improve the pharmacokinetics of curcumin. Curcumin-loaded micelles were prepared by a nanoprecipitation method using mPEG 5kDa - b -p(HPMA-Bz) copolymers with varying molecular weight of the hydrophobic block (5.2, 10.0, and 17.1 kDa). At equal curcumin loading, micelles composed of mPEG 5kDa - b -p(HPMA-Bz) 17.1kDa showed better curcumin retention in both phosphate-buffered saline (PBS) and plasma at 37 °C than micelles based on block copolymers with smaller hydrophobic blocks. No change in micelle size was observed during 24 h incubation in plasma using asymmetrical flow field-flow fractionation (AF 4 ), attesting to particle stability. However, 22–49% of the curcumin loading was released from the micelles during 24 h from formulations with the highest to the lowest molecular weight p(HPMA-Bz), respectively, in plasma. AF 4 analysis further showed that the released curcumin was subsequently solubilized by albumin. In vitro analyses revealed that the curcumin-loaded mPEG 5kDa - b -p(HPMA-Bz) 17.1kDa micelles were internalized by different types of cancer cells, resulting in curcumin-induced cell death. Intravenously administered curcumin-loaded, Cy7-labeled mPEG 5kDa - b -p(HPMA-Bz) 17.1kDa micelles in mice at 50 mg curcumin/kg showed a long circulation half-life for the micelles ( t 1/2 = 42 h), in line with the AF 4 results. In contrast, the circulation time of curcumin was considerably shorter than that of the micelles ( t 1/2α = 0.11, t 1/2β = 2.5 h) but ∼5 times longer than has been reported for free curcumin ( t 1/2α = 0.02 h). The faster clearance of curcumin in vivo compared to in vitro studies can be attributed to the interaction of curcumin with blood cells. Despite the excellent solubilizing effect of these micelles, no cytostatic effect was achieved in neuroblastoma-bearing mice, possibly because of the low sensitivity of the Neuro2A cells to curcumin.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

In Vitro and In Vivo Studies on HPMA-Based Polymeric Micelles Loaded with Curcumin

et al. 2021

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“…The low oral bioavailability F observed in mice could be related to a high first pass effect following oral dosing, among other factors such as subtract to efflux transporters or low gastrointestinal permeability (Kwan, 1997 ; Martinez and Amidon, 2002 ) which should be investigated. The oral bioavailability determined for IQG-607 cannot be used to rule out this anti-TB candidate because there are various drug candidates and also commercially available drugs that exhibit low oral bioavailability, such as SQ109 ( F = 4%) (Jia et al, 2005 ) and buspirone (F = 3.9%) (Brown and Tomlin, 2010 ). Several studies show that other determinants for the clinical outcome of a chemical compound have to be taken into consideration such as the drug candidate levels at the target site (Ryan, 1993 ; Presant et al, 1994 ; Joukhadar et al, 2001 ; Jia et al, 2005 ).…”

Section: Methods For Quantification and Pharmacokinetic Studiesmentioning

confidence: 99%

Is IQG-607 a Potential Metallodrug or Metallopro-Drug With a Defined Molecular Target in Mycobacterium tuberculosis?

et al. 2018

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The emergence of strains of Mycobacterium tuberculosis resistant to isoniazid (INH) has underscored the need for the development of new anti-tuberculosis agents. INH is activated by the mycobacterial katG-encoded catalase-peroxidase, forming an acylpyridine fragment that is covalently attached to the C4 of NADH. This isonicotinyl-NAD adduct inhibits the activity of 2-trans-enoyl-ACP(CoA) reductase (InhA), which plays a role in mycolic acid biosynthesis. A metal-based INH analog, Na3[FeII(CN)5(INH)]·4H2O, IQG-607, was designed to have an electronic redistribution on INH moiety that would lead to an intramolecular electron transfer to bypass KatG activation. HPLC and EPR studies showed that the INH moiety can be oxidized by superoxide or peroxide yielding similar metabolites and isonicotinoyl radical only when associated to IQG-607, thereby supporting redox-mediated drug activation as a possible mechanism of action. However, IQG-607 was shown to inhibit the in vitro activity of both wild-type and INH-resistant mutant InhA enzymes in the absence of KatG activation. IQG-607 given by the oral route to M. tuberculosis-infected mice reduced lung lesions. Experiments using early and late controls of infection revealed a bactericidal activity for IQG-607. HPLC and voltammetric methods were developed to quantify IQG-607. Pharmacokinetic studies showed short half-life, high clearance, moderate volume of distribution, and low oral bioavailability, which was not altered by feeding. Safety and toxic effects of IQG-607 after acute and 90-day repeated oral administrations in both rats and minipigs showed occurrence of mild to moderate toxic events. Eight multidrug-resistant strains (MDR-TB) were resistant to IQG-607, suggesting an association between katG mutation and increasing MIC values. Whole genome sequencing of three spontaneous IQG-607-resistant strains harbored katG gene mutations. MIC measurements and macrophage infection experiments with a laboratorial strain showed that katG mutation is sufficient to confer resistance to IQG-607 and that the macrophage intracellular environment cannot trigger the self-activation mechanism. Reduced activity of IQG-607 against an M. tuberculosis strain overexpressing S94A InhA mutant protein suggested both the need for KatG activation and InhA as its target. Further efforts are suggested to be pursued toward attempting to translate IQG-607 into a chemotherapeutic agent to treat tuberculosis.

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“…Major routes: Kidneys, Liver and Lungs Minor routes: Skin, hair, sweat, saliva, tears and milk [6,11,[27][28][29][30].…”

Section: Excretory Organsmentioning

confidence: 99%

Basics of Biopharmaceutics: A Mini Review

S¹

2017

BEBA

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Drug research is a unique multidisciplinary process towards the development of novel therapeutic agent to meet the current global medicinal needs. Drug discovery and development are the two major stages in drug research. Drug discovery includes new target identification and characterization, synthesis of new lead molecules, physicochemical characterization and screening of the lead molecule for its biological activity through in vitro and in vivo techniques. Drug development stage includes the assessment of its safety and toxicity of the developed new drug molecule. Drug molecules are substance used for diagnosis or treating for various diseases. Drugs can be given in different dosage form such as solids, semisolids, liquids, topical and parenteral preparation to produce the desired therapeutic activity and to meet the patient's needs. Biopharmaceutics is a major branch in pharmaceutical sciences describes the role of dosage form in the absorption and disposition of drugs in the body which are assessed through pharmacodynamic and pharmacokinetic parameters or properties. Pharmacodynamics correlates the concentration of the drug with its therapeutic and toxicological effect. Pharmacokinetics correlates how the drug moves through the human body by its four main pathways such as absorption, distribution, metabolism and elimination and measuring the drug concentration in biological matrices.

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Pharmacokinetic Principles

Cited by 4 publications

References 19 publications

In Vitro and In Vivo Studies on HPMA-Based Polymeric Micelles Loaded with Curcumin

In Vitro and In Vivo Studies on HPMA-Based Polymeric Micelles Loaded with Curcumin

Is IQG-607 a Potential Metallodrug or Metallopro-Drug With a Defined Molecular Target in Mycobacterium tuberculosis?

Basics of Biopharmaceutics: A Mini Review

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