Plasma protein binding (PPB) of corticosteroids (CS): Reappraisal of its significance in systemic pharmacological activity

Daley-Yates, PT; Harker, A.J.; Taylor, Simon; Daniel, M.J.

doi:10.1016/j.jaci.2004.12.030

Cited by 8 publications

(9 citation statements)

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“…A prolonged pulmonary residence time is apparent when the elimination half-life following inhaled administration is significantly longer than found following intravenous administration. This tendency has been noted for the more lipophilic inhaled corticosteroids, with the following order of lung retention times: FF >> MF ≥ FP > TAA >> BUD ≥ [7,21,23,45,52,42] For beclomethasone dipropionate (BDP) and ciclesonide (CIC), values in parenthesis are for the active metabolites -beclomethasone 17-monopropionate (BMP) and desisobutyryl ciclesonide (des-CIC). Glucocorticoid receptor binding affinity is relative to dexamethasone where dexamethasone affinity = 100.…”

Section: Introductionmentioning

confidence: 84%

Inhaled corticosteroids: potency, dose equivalence and therapeutic index

Daley‐Yates

2015

Brit J Clinical Pharma

209

189

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Glucocorticosteroids are a group of structurally related molecules that includes natural hormones and synthetic drugs with a wide range of anti-inflammatory potencies. For synthetic corticosteroid analogues it is commonly assumed that the therapeutic index cannot be improved by increasing their glucocorticoid receptor binding affinity. The validity of this assumption, particularly for inhaled corticosteroids, has not been fully explored. Inhaled corticosteroids exert their anti-inflammatory activity locally in the airways, and hence this can be dissociated from their potential to cause systemic adverse effects. The molecular structural features that increase glucocorticoid receptor binding affinity and selectivity drive topical anti-inflammatory activity. However, in addition, these structural modifications also result in physicochemical and pharmacokinetic changes that can enhance targeting to the airways and reduce systemic exposure. As a consequence, potency and therapeutic index can be correlated. However, this consideration is not reflected in asthma treatment guidelines that classify inhaled corticosteroid formulations as low-, mid- and high dose, and imbed a simple dose equivalence approach where potency is not considered to affect the therapeutic index. This article describes the relationship between potency and therapeutic index, and concludes that higher potency can potentially improve the therapeutic index. Therefore, both efficacy and safety should be considered when classifying inhaled corticosteroid regimens in terms of dose equivalence. The historical approach to dose equivalence in asthma treatment guidelines is not appropriate for the wider range of molecules, potencies and device/formulations now available. A more robust method is needed that incorporates pharmacological principles.

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Section: Introductionmentioning

confidence: 84%

Inhaled corticosteroids: potency, dose equivalence and therapeutic index

Daley‐Yates

2015

Brit J Clinical Pharma

209

189

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“…2004). Also, independent data from two research groups have shown that mometasone furoate, but none of the other steroids tested including fluticasone propionate, binds to the progesterone receptor with high affinity (Daley‐Yates et al . 2005).…”

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confidence: 99%

Airway Selectivity: An Update of Pharmacokinetic Factors Affecting Local and Systemic Disposition of Inhaled Steroids

Edsbäcker

Johansson

2006

Basic Clin Pharma Tox

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Topical corticosteroids remain the most efficacious single treatment for asthma and rhinitis, despite the emergence of newer drugs in recent years. The antiinflammatory properties of these products, combined with the targeting of formulations and optimization of the intrinsic pharmacokinetic features of the newer corticosteroid molecules has resulted in substantially improved airway selectivity. This review sets out to summarize the pharmacokinetic properties of inhaled corticosteroids that are important for the achievement of high levels of airway selectivity, with additional focus on the use of prodrugs/softdrugs relative to those of conventional corticosteroid molecules, mechanisms (such as esterification) by which retention at the target site is achieved while minimizing systemic exposure, and the role of plasma protein binding.

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“…These results clarify two issues, brought up by some investigators, within the context of new glucocorticoids with high receptor affinity and pronounced plasma and tissue binding. First, the reduced receptor occupancy for des-CIC does not support the hypothesis of some investigators that the "extremely" high affinity of newer glucocorticoids will strip the drug from low affinity binding sites such as albumin or lung binding components, and, consequently, the degree of receptor occupancy will not depend on tissue binding (Daley-Yates et al, 2005). Second, increased lung tissue binding has never been critically evaluated as a factor that might potentially affect the clinical outcome at a given dose.…”

Section: Compoundmentioning

confidence: 89%

“…This study evaluated the importance of tissue and plasma protein binding for inhaled glucocorticoids as a response to suggestions that a high protein binding will reduce systemic side effects and be beneficial for topical targeting (Esmailpour et al, 2000) or not affect local and systemic effects (Daley-Yates et al, 2005). All the synthetic glucocorticoids lack affinity to the high affinity protein transcortin (Ballard, 1979) but bind to albumin with low affinity.…”

Section: Discussionmentioning

confidence: 99%

“…This argues against the possibility of maintaining a "slow release" depot under "sink" conditions (reduction in drug concentrations). Other authors have suggested that the increase in tissue and plasma binding for the newer glucocorticoids will not lead to a reduced antiasthmatic effect because the bound steroid would be stripped from these sites by the extremely high affinity receptors (Daley-Yates et al, 2005). A similar hypothesis was formulated by Van Der Graaf et al (1997) and van Steeg et al (2005) (PAGE, http:// www.page-meeting.org/?abstractϭ788) to explain results of a pharmacokinetic/pharmacodynamic (PK/PD) analysis for propranolol in which receptor occupancy was better described by total and not free drug concentrations.…”

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confidence: 99%

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Budesonide and Ciclesonide: Effect of Tissue Binding on Pulmonary Receptor Binding

Wu¹,

Blomgren²,

Ekholm³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Newer inhaled glucocorticoids often show low systemic side effects because of their high protein binding. This study was interested in evaluating the effects of increased plasma protein and tissue binding on pulmonary receptor occupancy. Rats received des-ciclesonide (des-CIC; the active metabolite of the prodrug ciclesonide) and budesonide (BUD; a drug with lower protein binding but similar receptor affinity) as constant rate infusion over 6 h (intravenous bolus of 30 g/kg, followed by 10 g/h/kg over 6 h). Total and free glucocorticoid concentration in plasma and tissues, as well as the number of occupied lung glucocorticoid receptors, was determined. A pharmacokinetic/pharmacodynamic (PK/PD) model investigated the effects of varying plasma and tissue binding on pulmonary and systemic receptor occupancy after inhalation. After constant rate infusion, the total drug concentration in tissues and plasma was comparable for both drugs, whereas the free concentration of des-CIC in all the tissues and plasma was one fifth to one seventh that of BUD. This translated into lower receptor occupancy in the lung for des-CIC (49 ؎ 11%) than for BUD (94 ؎ 8%). The PK/PD model predicted lower receptor occupancy in the lung and the systemic tissues when a drug with pronounced binding was inhaled. Glucocorticoids with higher plasma and tissue binding might show not only lower systemic side effects but also reduced efficacy in the lung when given in a similar microgram dose.

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Plasma protein binding (PPB) of corticosteroids (CS): Reappraisal of its significance in systemic pharmacological activity

Cited by 8 publications

References 0 publications

Inhaled corticosteroids: potency, dose equivalence and therapeutic index

Inhaled corticosteroids: potency, dose equivalence and therapeutic index

Airway Selectivity: An Update of Pharmacokinetic Factors Affecting Local and Systemic Disposition of Inhaled Steroids

Budesonide and Ciclesonide: Effect of Tissue Binding on Pulmonary Receptor Binding

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