Prediction of Pharmacokinetics Prior to In Vivo Studies. II. Generic Physiologically Based Pharmacokinetic Models of Drug Disposition

Poulin, Patrick; Theil, Frank‐Peter

doi:10.1002/jps.10128

Cited by 279 publications

(207 citation statements)

References 18 publications

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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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“…The vast majority of current generic PBPK models is build on a lumped, wellstirred tissue compartment model (e.g., (1,23,24)) using K t:p or K t:up as an input parameter.…”

Section: Methodsmentioning

confidence: 99%

“…Typically, tissue volume is regarded as extra-vascular space, comprising the interstitial and the cellular space, while the organ space includes the vascular space in addition to the interstitial and cellular space. Tissue volume data can be found in the literature, see e.g., (1,12,16,29). In (18, Table A2), values for the vascular volume fractions V v:org and for the interstitial volume fractions V i:org of diverse organs have been published for rats and assumed to be identical for humans.…”

Section: Parameterization Of the Sub-compartmentalized Tissue Distribmentioning

confidence: 99%

“…Physiologically based pharmacokinetic (PBPK) modelling and simulation is increasingly recognized and used as a supporting tool in drug discovery and development (1)(2)(3)(4)(5)(6). The aim is to analyze, interpret and predict the pharmacokinetics of drug candidates in the different stages of drug discovery and development (7,8).…”

Section: Introductionmentioning

confidence: 99%

“…The extent of drug distribution into the tissue constituents is then estimated from readily available in vitro data. Utilizing these achievements, generic PBPK models have been designed that can be used in early drug discovery (1)(2)(3)15). Subsequent predictive models (12,16,17) rely on the same idea, but differ in the way the tissue is composed and/or the distribution into the different constituents is approximated.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

Kleist

Huisinga²

2007

J Pharmacokinet Pharmacodyn

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We present a sub-compartmentalized model of drug distribution in tissue that extends existing approaches based on the well-stirred tissue model. It is specified in terms of differential equations that explicitly account for the drug concentration in erythrocytes, plasma, interstitial and cellular space. Assuming, in addition, steady state drug distribution and by lumping the different sub-compartments, established models to predict tissue-plasma partition coefficients can be derived in an intriguingly simple way. This direct link is exploited to explicitly construct and parameterize the sub-compartmentalized model for moderate to strong bases, acids, neutrals and zwitterions. The derivation highlights the contributions of the different tissue constituents and provides a simple and transparent framework for the construction of novel tissue distribution models.

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Molecular Modeling in Drug Design

Marshall

Beusen²

2003

Burger's Medicinal Chemistry and Drug Discovery

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This chapter examines the approaches to molecular modeling and drug design and emphasizes their limitations. Useful information to guide the design and synthesis of potential novel therapeutics can be developed from an analysis of structure‐activity data in the three‐dimensional framework provided by current molecular modeling techniques. Although most of the techniques and approaches described have broader application than shown, the examples chosen should be sufficient to illustrate their use.

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Prediction of Pharmacokinetics Prior to In Vivo Studies. II. Generic Physiologically Based Pharmacokinetic Models of Drug Disposition

Cited by 279 publications

References 18 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

Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

Molecular Modeling in Drug Design

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