The binding of flurbiprofen to plasma proteins

Aarons, Leon; Khan, Abdul Haleem; Grennan, D M; Alam-Siddiqi, M

doi:10.1111/j.2042-7158.1985.tb05101.x

Cited by 11 publications

(2 citation statements)

References 6 publications

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“…The amounts of FBF distributed into the muscle after oral administration were still significantly lower than those after iontophoresis at 0.5 h and 1 h after the initiation of drug administration: 0.13 ± 0.05 μg/g for Oral 0.5 h vs. 1.87 ± 0.41 μg/g at Ionto 0.5 h, and 0.28 ± 0.11 μg/g for Oral 1.5 h vs. 0.93 ± 0.35 μg/g at Ionto 0.5 h + 1 h. Nevertheless, tissue concentrations represented a larger proportion of systemic exposure than the levels detected in plasma [ 27 ]. Given the high plasma protein binding rate (> 99%) [ 28 ] and relatively low apparent volume of distribution (0.12 L/kg in human [ 29 ], and about 0.11 ~ 0.16 L/kg in rats [ 30 ]), orally administered FBF is unlikely to enable fast drug distribution in local superficial tissues within short time.…”

Section: Resultsmentioning

confidence: 99%

Tissue Levels of Flurbiprofen in the Rat Plantar Heel after Short-Duration Topical Iontophoresis Are Sufficient to Induce Pharmacodynamic Responses to Local Pain Stimuli

et al. 2020

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The objective of this study was to investigate the topical iontophoresis of flurbiprofen (FBF) as a means to enhance its local bioavailability and thereby provide an improved and targeted treatment of plantar heel pain. Initial in vitro experiments using porcine ear skin investigated iontophoretic transport of FBF under different conditions. Local FBF biodistribution in the rat paw in vivo was compared after topical or oral administration. Efficacy of pain management was investigated using a plantar incisional model by evaluating pharmacodynamic responses to local pain stimuli. The results demonstrated that iontophoresis of FBF significantly increased cutaneous deposition and transdermal permeation of FBF as compared to passive delivery—it also enabled drug input to be controlled by modulation of current density and drug concentration (r2 > 0.99). Topical iontophoresis of FBF in vivo enabled higher drug levels in skin and muscle in rat plantar aspect and superior pharmacodynamic responses to local pain stimuli, in comparison to oral and passive delivery. In conclusion, short-duration topical iontophoresis of FBF may better help to relieve plantar heel pain than oral or passive administration, which should be of clinical interest.

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Section: Resultsmentioning

confidence: 99%

Tissue Levels of Flurbiprofen in the Rat Plantar Heel after Short-Duration Topical Iontophoresis Are Sufficient to Induce Pharmacodynamic Responses to Local Pain Stimuli

et al. 2020

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“…Simulations were performed using the virtual North European Caucasian and Chinese healthy volunteer populations of the software. [55,60], while the values for the blood/plasma concentration ratio (B:P) and the fraction unbound (f u ) are 0.55 and 0.01, respectively [5,[56][57][58][59].…”

Section: Pbpk Model Development and Verificationmentioning

confidence: 99%

Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling to Predict the Impact of CYP2C9 Genetic Polymorphisms, Co-Medication and Formulation on the Pharmacokinetics and Pharmacodynamics of Flurbiprofen

Loisios-Konstantinidis

Cristofoletti

Jamei

et al. 2020

Pharmaceutics

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Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models can serve as a powerful framework for predicting the influence as well as the interaction of formulation, genetic polymorphism and co-medication on the pharmacokinetics and pharmacodynamics of drug substances. In this study, flurbiprofen, a potent non-steroid anti-inflammatory drug, was chosen as a model drug. Flurbiprofen has absolute bioavailability of ~95% and linear pharmacokinetics in the dose range of 50–300 mg. Its absorption is considered variable and complex, often associated with double peak phenomena, and its pharmacokinetics are characterized by high inter-subject variability, mainly due to its metabolism by the polymorphic CYP2C9 (fmCYP2C9 ≥ 0.71). In this study, by leveraging in vitro, in silico and in vivo data, an integrated PBPK/PD model with mechanistic absorption was developed and evaluated against clinical data from PK, PD, drug-drug and gene-drug interaction studies. The PBPK model successfully predicted (within 2-fold) 36 out of 38 observed concentration-time profiles of flurbiprofen as well as the CYP2C9 genetic effects after administration of different intravenous and oral dosage forms over a dose range of 40–300 mg in both Caucasian and Chinese healthy volunteers. All model predictions for Cmax, AUCinf and CL/F were within two-fold of their respective mean or geometric mean values, while 90% of the predictions of Cmax, 81% of the predictions of AUCinf and 74% of the predictions of Cl/F were within 1.25 fold. In addition, the drug-drug and drug-gene interactions were predicted within 1.5-fold of the observed interaction ratios (AUC, Cmax ratios). The validated PBPK model was further expanded by linking it to an inhibitory Emax model describing the analgesic efficacy of flurbiprofen and applying it to explore the effect of formulation and genetic polymorphisms on the onset and duration of pain relief. This comprehensive PBPK/PD analysis, along with a detailed translational biopharmaceutic framework including appropriately designed biorelevant in vitro experiments and in vitro-in vivo extrapolation, provided mechanistic insight on the impact of formulation and genetic variations, two major determinants of the population variability, on the PK/PD of flurbiprofen. Clinically relevant specifications and potential dose adjustments were also proposed. Overall, the present work highlights the value of a translational PBPK/PD approach, tailored to target populations and genotypes, as an approach towards achieving personalized medicine.

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Contributions of Plasma Protein Binding and Membrane Transporters to Drug‐Induced Mitochondrial Toxicity

McStay

2018

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants

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The binding of flurbiprofen to plasma proteins

Cited by 11 publications

References 6 publications

Tissue Levels of Flurbiprofen in the Rat Plantar Heel after Short-Duration Topical Iontophoresis Are Sufficient to Induce Pharmacodynamic Responses to Local Pain Stimuli

Tissue Levels of Flurbiprofen in the Rat Plantar Heel after Short-Duration Topical Iontophoresis Are Sufficient to Induce Pharmacodynamic Responses to Local Pain Stimuli

Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling to Predict the Impact of CYP2C9 Genetic Polymorphisms, Co-Medication and Formulation on the Pharmacokinetics and Pharmacodynamics of Flurbiprofen

Contributions of Plasma Protein Binding and Membrane Transporters to Drug‐Induced Mitochondrial Toxicity

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