Plasma Protein Binding in Drug Discovery and Development

Howard, Monique L.; Hill, John J.; Galluppi, Gerald R.; McLean, Matthew A.

doi:10.2174/138620710790596745

Cited by 131 publications

(127 citation statements)

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“…Overall, no clear correlation with plasma albumin concentrations was measurable (58). Remarkably, the voriconazole PPB values were highly deviant from our previously published in vitro data, from the data published by Roffey et al (59), and from the results in this study, which were all generated by ED, in our opinion still the gold standard in determining protein binding of drugs (34,(60)(61)(62). Moreover, the most important factors possibly influencing the performance of the ED procedure, such as environmental temperature, pH, mass balance, and volume shift, were ruled out (23), resulting in a robust and reliable method for determining voriconazole PPB.…”

Section: Discussioncontrasting

confidence: 81%

Impact of Hypoalbuminemia on Voriconazole Pharmacokinetics in Critically Ill Adult Patients

Vanstraelen

Wauters

Vercammen

et al. 2014

Antimicrob Agents Chemother

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f Setting the adequate dose for voriconazole is challenging due to its variable pharmacokinetics. We investigated the impact of hypoalbuminemia (<35 g/liter) on voriconazole pharmacokinetics in adult intensive care unit (ICU) patients treated with voriconazole (20 samples in 13 patients) as well as in plasma samples from ICU patients that had been spiked with voriconazole at concentrations of 1.5 mg/liter, 2.9 mg/liter, and 9.0 mg/liter (66 samples from 22 patients). Plasma albumin concentrations ranged from 13.8 to 38.7 g/liter. Total voriconazole concentrations in adult ICU patients treated with voriconazole ranged from 0.5 to 8.7 mg/liter. Unbound and bound voriconazole concentrations were separated using high-throughput equilibrium dialysis followed by liquid chromatography-tandem mass spectrometry (LC-MSMS). Multivariate analysis revealed a positive relationship between voriconazole plasma protein binding and plasma albumin concentrations (P < 0.001), indicating higher unbound voriconazole concentrations with decreasing albumin concentrations. The correlation is more pronounced in the presence of elevated bilirubin concentrations (P ‫؍‬ 0.05). We therefore propose to adjust the measured total voriconazole concentrations in patients with abnormal plasma albumin and total serum bilirubin plasma concentrations who show adverse events potentially related to voriconazole via a formula that we developed. Assuming 50% protein binding on average and an upper limit of 5.5 mg/liter for total voriconazole concentrations, the upper limit for unbound voriconazole concentrations is 2.75 mg/liter. Alterations in voriconazole unbound concentrations caused by hypoalbuminemia and/or elevated bilirubin plasma concentrations cannot be countered immediately, due to the adult saturated hepatic metabolism. Consequently, increased unbound voriconazole concentrations can possibly cause adverse events, even when total voriconazole concentrations are within the reference range.

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Section: Discussioncontrasting

confidence: 81%

Impact of Hypoalbuminemia on Voriconazole Pharmacokinetics in Critically Ill Adult Patients

Vanstraelen

Wauters

Vercammen

et al. 2014

Antimicrob Agents Chemother

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“…The samples were left to equilibrate at 37°C but a temperature controlled centrifuge was not available meaning that the sample temperature would have dropped somewhat during ultrafiltration. The fu of some drugs has been reported to rise with increasing temperature [20], but this is unlikely to be a significant issue in our study since previous reports used higher temperatures, and our fu values were slightly larger. Further, pH was not controlled, which is frequently the case with ultrafiltration [21].…”

Section: Discussioncontrasting

confidence: 65%

Adult age and ex vivo protein binding of lorazepam, oxazepam and temazepam in healthy subjects

Chin

Jensen

Larsen

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The hypothesis that protein binding decreases with ageing has been used to explain studies that have not found a decline in total clearance in relation to age of highly protein bound drugs, cleared by capacity limited metabolism.• Lorazepam, oxazepam and temazepam are highly protein bound to albumin and are cleared by capacity limited metabolism. • There is conflicting or little data concerning the relationship between the protein binding of these drugs and age. WHAT THIS PAPER ADDS• In an ex vivo study of 60 healthy subjects (19-87 years), no clinically significant change was seen in the protein binding of these benzodiazepines with age, arguing against the hypothesis, at least in healthy subjects. The study was adequately powered to show a change of at least 7-10%. AIMTo see if adult age correlates with ex vivo protein binding of lorazepam, oxazepam and temazepam in healthy subjects. METHODSSixty healthy drug free subjects were recruited in the age groups 18-39, 40-64 and Ն65 years. Plasma albumin concentrations were determined. Ex vivo unbound fractions (fu) were assessed by spiking samples and measuring the free and total concentrations. RESULTSNo correlation of age with fu was seen. The study was powered to demonstrate a change in fu of Ն7-10%. A decline in plasma albumin concentration of~0.03 g l -1 year -1 was seen with increasing age (P = 0.032) and was associated with increased fu of lorazepam (P = 0.009) and oxazepam (P = 0.014). CONCLUSIONSThere was no association of adult age with ex vivo fu of lorazepam, oxazepam or temazepam in healthy subjects.

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“…As a result, membrane binding and fluid shifts need not be considered. Following centrifugation, a sample partitions into three layers: a top layer containing very-low-density lipoproteins and chylomicrons; a middle aqueous layer, which is protein free; and a bottom layer, which contains larger plasma proteins and lipoproteins (50). f U can be calculated by comparing the C T obtained prior to centrifugation and the C U obtained from the aqueous, middle layer.…”

Section: Protein Binding Determinationmentioning

confidence: 99%

“…f U can be calculated by comparing the C T obtained prior to centrifugation and the C U obtained from the aqueous, middle layer. A major disadvantage of the method is that it is relatively low throughput, limiting how many samples may be processed at once (50).…”

Section: Protein Binding Determinationmentioning

confidence: 99%

Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents

2013

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SUMMARY For the optimization of dosing regimens of anti-infective agents, it is imperative to have a good understanding of pharmacokinetics (PK) and pharmacodynamics (PD). Whenever possible, drug efficacy needs to be related to unbound concentrations at the site of action. For anti-infective drugs, the infection site is typically located outside plasma, and a drug must diffuse through capillary membranes to reach its target. Disease- and drug-related factors can contribute to differential tissue distribution. As a result, the assumption that the plasma concentration of drugs represents a suitable surrogate of tissue concentrations may lead to erroneous conclusions. Quantifying drug exposure in tissues represents an opportunity to relate the pharmacologically active concentrations to an observed pharmacodynamic parameter, such as the MIC. Selection of an appropriate specimen to sample and the advantages and limitations of the available sampling techniques require careful consideration. Ultimately, the goal will be to assess the appropriateness of a drug and dosing regimen for a specific pathogen and infection.

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Plasma Protein Binding in Drug Discovery and Development

Cited by 131 publications

References 0 publications

Impact of Hypoalbuminemia on Voriconazole Pharmacokinetics in Critically Ill Adult Patients

Impact of Hypoalbuminemia on Voriconazole Pharmacokinetics in Critically Ill Adult Patients

Adult age and ex vivo protein binding of lorazepam, oxazepam and temazepam in healthy subjects

Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents

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