Changes in plasma protein binding have little clinical relevance

Benet, Leslie Z.; Hoener, Betty‐Ann

doi:10.1067/mcp.2002.121829

Cited by 715 publications

(459 citation statements)

References 13 publications

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“…For drugs with hepatic elimination, the effects of aging on phase I and phase II metabolism and transport are not easily quantified in order to guide drug therapy. Potential changes in protein binding are not thought to be of major clinical significance in most cases,2 but changes in the intrinsic clearance of unbound drug can further complicate pharmacotherapy in the elderly 3…”

mentioning

confidence: 99%

Population Pharmacokinetics Modeling of Unbound Efavirenz, Atazanavir, and Ritonavir in HIV‐Infected Subjects With Aging Biomarkers

Dumond

Chen

Cottrell

et al. 2016

CPT Pharmacom & Syst Pharma

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Unbound drug is the pharmacodynamically relevant concentration. This study aimed to determine if chronologic age or markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression, altered unbound pharmacokinetics (PKs) of efavirenz (EFV) and atazanavir/ritonavir (ATV/RTV). Sixty human immunodeficiency virus (HIV)‐infected participants receiving EFV and 31 receiving ATV/RTV provided 1 to 11 samples to quantify total and unbound plasma concentrations. Population PK models with total and unbound concentrations simultaneously described are developed for each drug. The unbound fractions for EFV, ATV, and RTV are 0.65%, 5.67%, and 0.63%, respectively. Covariate analysis suggests RTV unbound PK is sensitive to body size; unbound fraction of RTV is 34% lower with body mass index (BMI) above 30 kg/m2. No alterations in drug clearance or unbound fraction with age, frailty, or p16INK4a expression were observed. Assessing functional and physiologic aging markers to inform potential PK changes is necessary to determine if drug/dosing changes are warranted in the aging population.

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mentioning

confidence: 99%

Population Pharmacokinetics Modeling of Unbound Efavirenz, Atazanavir, and Ritonavir in HIV‐Infected Subjects With Aging Biomarkers

Dumond

Chen

Cottrell

et al. 2016

CPT Pharmacom & Syst Pharma

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“…Except for drugs with a very high binding strength, changes in plasma protein binding have limited clinical effects [17].…”

Section: Discussionmentioning

confidence: 99%

Influence of acute normovolemic hemodilution on the potency and time course of action of rocuronium in rabbits

Lee

Kim

et al. 2016

Anesth Pain Med

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Background:We performed this study to evaluate the potency and time course of rocuronium-induced neuromuscular block following moderate or severe acute normovolemic hemodilution (ANH) in rabbits. Methods: Forty five rabbits were randomly assigned to the control (C) group, the moderate ANH (M) group, or the severe ANH (S) group. After stabilization of sevoflurane anesthesia, ANH was achieved by drainage of arterial blood and an intravenous infusion of 6% hydroxyethyl starch, during which hematocrit (Hct) decreased to 26.2 ± 2.5% in the M group and 17.6 ± 2.2% in the S group. We determined dose-response relationships of rocuronium in the three groups and created a time course of the action of 0.6 mg/kg rocuronium. Results: The 50% effective dose (ED50) for rocuronium was 45% and 50% lower in the M and S groups, respectively, than in the C group (50.9 ± 6.3 g/kg) (P ＜ 0.001). The onset time after 0.6 mg/kg rocuronium was faster in the ANH groups compared with the C group (P ＜ 0.001). The duration of neuromuscular block was prolonged by 38% and 43% in the M and S groups, respectively, compared with the C group (49.1 ± 6.9 min) (P ＜ 0.001). Conclusions: ANH resulted in high potency, rapid onset, and prolonged duration of rocuronium. However, the severity of ANH did not alter the potency and duration of action of rocuronium.

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“…An increase in volume (V d ) with age partly can be explained by the 10% decrease in PB% with both increasing age (10,42) and kidney impairment (34,35). Free plasma fraction (f p ) will increase with decreasing PB%, where plasma (V p ) and tissue volume (V t ) stay constant.…”

Section: Plasma Bindingmentioning

confidence: 99%

“…The considerable changes in pharmacokinetic parameters with alterations in PB% do not lead to proportional changes in the pharmacodynamic effects of protein-bound drugs (e.g., methylprednisolone). Alterations that affect PB% only have little clinical relevance for drug dosing (35), because the drug effect is assumed to be exerted by the free drug concentration (C free ) that stays constant on average.…”

Section: Plasma Bindingmentioning

confidence: 99%

“…Impaired function of aging kidneys affects renal drug excretion but also cytochrome P450 activity (11), metabolic Cl (33), plasma binding (PB%) (34,35), tissue binding (36), and thereby absorption, distribution, and elimination processes of many drugs; therefore, measured pharmacokinetic parameters are needed for the elderly.…”

Section: Pharmacokinetics In the Elderlymentioning

confidence: 99%

See 1 more Smart Citation

Review on Pharmacokinetics and Pharmacodynamics and the Aging Kidney

Aymanns¹,

Keller²,

Maus³

et al. 2010

Clinical Journal of the American Society of Nephrology

130

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In people who are aged >65 years, pharmacokinetics are influenced more by the loss of kidney function than by the aging process of any other organ. A GFR of 30 to 60 ml/min, suggestive of stage 3 kidney disease, is observed in 15 to 30% of elderly people. Drug dosing must be adjusted to both changing pharmacokinetics and pharmacodynamics; the pharmacodynamics might be influenced by the aging of other organs, too. Using our NEPharm database, we extracted abstracts with pharmacokinetic parameters since 1999 from a weekly PubMed search. The recorded data were analyzed and compared with published recommendations on drug dosage and use in the elderly. Purely age-related changes in pharmacokinetic parameters were recorded from publications on 127 drugs. The analysis of our NEPharm records revealed an average (mean ؎ SD) age-related prolongation of half-life of 1.39-fold (corresponding to ؉39 ؎ 61%). Contrasting to common opinion, mean changes in clearance (؊1 ؎ 54%) and volume of distribution (؉24 ؎ 56%) were even less. The modest changes in pharmacokinetics do not suggest general dosage modifications in the elderly for most drugs. Changes in pharmacodynamics justify the common medication rule in the elderly-"start low ؉ go slow"-especially for drugs that act on the central nervous system; however, in the case of anti-infective and anticancer therapy, the rule should be "hit hard ‫؍‬ start high ؉ go fast" to produce the target effect also in the elderly.

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Changes in plasma protein binding have little clinical relevance

Abstract: Clinical Pharmacology & Therapeutics (2002) 71, 115–121; doi:

Cited by 715 publications

References 13 publications

Population Pharmacokinetics Modeling of Unbound Efavirenz, Atazanavir, and Ritonavir in HIV‐Infected Subjects With Aging Biomarkers

Population Pharmacokinetics Modeling of Unbound Efavirenz, Atazanavir, and Ritonavir in HIV‐Infected Subjects With Aging Biomarkers

Influence of acute normovolemic hemodilution on the potency and time course of action of rocuronium in rabbits

Review on Pharmacokinetics and Pharmacodynamics and the Aging Kidney

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