A hybrid approach to advancing quantitative prediction of tissue distribution of basic drugs in human

Poulin, Patrick; Ekins, Sean; Theil, Frank‐Peter

doi:10.1016/j.taap.2010.10.014

Cited by 35 publications

(50 citation statements)

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“…The distribution of a drug among tissues is characterized by the Kp value which is defined as the ratio of the total concentration of compound in the tissue to the total concentration of compound in the plasma at steady state [4]. Although there are approaches to estimate a priori the steady-state Kp values, the measured tissue data remain of the greatest value [4][5][6][7]. There are studies reporting the correlation between tissue-to-blood partition coefficients in rats obtained in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Tylutki

Polak

2015

Biopharm & Drug Disp

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ABSTRACT:Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart.

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Section: Introductionmentioning

confidence: 99%

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Tylutki

Polak

2015

Biopharm & Drug Disp

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“…b A blood/plasma concentration ratio of 3.5 was used in the calculation because plasma concentrations were Ͻ100 ng/ml in the clinical study with UK-390957. acidic phospholipids (e.g., carbonic anhydrase, hemoglobin, or cyclophilin) or if increased partitioning occurs due to drug-induced phospholipidosis (Poulin et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The affinity of a compound to acidic phospholipids was not measured directly but rather was estimated from the blood/plasma concentration ratio (BPR) (Rodgers et al, 2005a), taking advantage of the fact that the blood cells contain acidic phospholipids. The estimates of V ss obtained using the approach described by Rodgers et al, although generally showing an improvement in accuracy for basic drugs, is sensitive to the accuracy of the BPR measurement and can be inaccurate if a compound binds significantly to components other than acidic phospholipids within blood cells (Rodgers et al, 2005b;Poulin et al, 2011).With this limitation in mind, we investigated the feasibility of directly measuring the binding of basic compounds to acidic phospholipids using a surface plasmon resonance approach. The dissociation constant, K D , obtained using this approach was incorporated into a mechanistic physiologically based pharmacokinetic model, and the accuracy of predicted V ss was compared with the data obtained after intravenous administration of the compounds to humans.…”

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Measurement of Binding of Basic Drugs to Acidic Phospholipids Using Surface Plasmon Resonance and Incorporation of the Data into Mechanistic Tissue Composition Equations to Predict Steady-State Volume of Distribution

Small

Gardner²,

Jones³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Acidic phospholipid binding plays an important role in determining the tissue distribution of basic drugs. This article describes the use of surface plasmon resonance to measure binding affinity (K D ) of three basic drugs to phosphatidylserine, a major tissue acidic phospholipid. The data are incorporated into mechanistic tissue composition equations to allow prediction of the steady-state volume of distribution (V ss ). The prediction accuracy of V ss using this approach is compared with the original methodology described by Rodgers et al. (J Pharm Sci 94:1259-1276), in which the binding to acidic phospholipids is calculated from the blood/plasma concentration ratio (BPR). The compounds used in this study [amlodipine, propranolol, and 3-dimethylaminomethyl-4-(4-methylsulfanylphenoxy)-benzenesulfonamide (UK-390957)] showed higher affinity binding to phosphatidylserine than to phosphatidylcholine. When the binding affinity to phosphatidylserine was incorporated into mechanistic tissue composition equations, the V ss was more accurately predicted for all three compounds by using the surface plasmon resonance measurement than by using the BPR to estimate acidic phospholipid binding affinity. The difference was particularly marked for UK-390957, a sulfonamide that has a high BPR due to binding to carbonic anhydrase. The novel approach described in this article allows the binding affinity of drugs to an acidic phospholipid (phosphatidylserine) to be measured directly and demonstrates the utility of the binding data in the prediction of V ss . IntroductionAlong with clearance, the volume of distribution at steady state (V ss ) is a key pharmacokinetic parameter that determines how long a drug remains in the body. Several approaches have been used to prospectively predict human V ss , including scaling in vivo data from preclinical species, scaling in vitro data, and various in silico calculation methods (Obach, 2007).An approach that has gained popularity in recent years is to use in vitro and physicochemical data for a particular compound to estimate its tissue/plasma partitioning and by accounting for the volumes of different tissues and their composition. This information is used to predict V ss of a compound in an integrated physiologically based manner (eq. 1).where V is physical tissue volume, T is tissue, Kp is tissue to plasma partition coefficient, and p is plasma.Prediction of Kp on the basis of tissue composition and the physicochemical properties of a compound was first described by Poulin and Theil (2000) for neutral compounds, with emphasis on lipophilicity and binding to neutral lipids. This approach has subsequently been used by various authors to predict V ss for different compound datasets (Jones et al., 2006;De Buck et al., 2007). An extension to this mechanistic PBPK model that incorporates pH and binding of the ionized base to acidic phospholipids as an additional component of tissue binding was proposed by Rodgers et al. (2005a), initially for ionized bases. The affinity of a compound t...

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“…The tissue composition-based equations described above have been designed to describe specific interactions. Recently, unified algorithms combining these different processes have been developed to facilitate their application (6,(46)(47)(48). Several studies have been performed to explore predictability of the different mechanistic approaches for Kp prediction using diverse drug datasets, with varying degrees of accuracy (8,10,11,(48)(49)(50)(51)(52)(53).…”

Section: Pbpk Model Methodologies Small Molecule Pbpk Modelsmentioning

confidence: 99%

Dose Selection Based on Physiologically Based Pharmacokinetic (PBPK) Approaches

Jones

Mayawala

Poulin³

2012

AAPS J

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Abstract. Physiologically based pharmacokinetic (PBPK) models are built using differential equations to describe the physiology/anatomy of different biological systems. Readily available in vitro and in vivo preclinical data can be incorporated into these models to not only estimate pharmacokinetic (PK) parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. They provide a mechanistic framework to understand and extrapolate PK and dose across in vitro and in vivo systems and across different species, populations and disease states. Using small molecule and large molecule examples from the literature and our own company, we have shown how PBPK techniques can be utilised for human PK and dose prediction. Such approaches have the potential to increase efficiency, reduce the need for animal studies, replace clinical trials and increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however some limitations need to be addressed to realise its application and utility more broadly.

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A hybrid approach to advancing quantitative prediction of tissue distribution of basic drugs in human

Cited by 35 publications

References 51 publications

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Measurement of Binding of Basic Drugs to Acidic Phospholipids Using Surface Plasmon Resonance and Incorporation of the Data into Mechanistic Tissue Composition Equations to Predict Steady-State Volume of Distribution

Dose Selection Based on Physiologically Based Pharmacokinetic (PBPK) Approaches

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