The Impact of Lipophilicity on Environmental Processes, Drug

Microchemical Journal 146 (2019) 393–406

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Microchemical Journal

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Review article The impact of lipophilicity on environmental processes, drug delivery and T bioavailability of food components ⁎ Tomasz Chmiela, , Anna Mieszkowskab, Dagmara Kempińska-Kupczyka, Agata Kot-Wasika, Jacek Namieśnika, Zofia Mazerskab a Department of Analytical Chemistry, Faculty of Chemistry, Gdansk University of Technology, 11/12 G. Narutowicza St., 80-233 Gdańsk, Poland b Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, 11/12 G. Narutowicza St., 80-233 Gdańsk, Poland

ARTICLE INFO ABSTRACT

Keywords: Lipophilic properties of the compound allow to predict its fate in living organisms and to propose the models of Lipophilicity descriptors chemicals transport and accumulation in the ecosystem. Lipophilicity is also useful as the characteristic of ADME chemicals in respect to their optimal attributes for specific biological and non-biological tasks. The lipophilicity Environmental fate descriptors define the potency of endo- and xenobiotics to metabolic transformations and their affinity to target Drug design proteins. Therefore, the lipophilicity optimization allows to find the optimal structure of drugs in quantitative QSAR studies structure-activity relationship (QSAR) studies. Additionally, lipophilicity governs the transport of chemicals in Food components bioavailability the environment and the food delivery systems of bioactive compounds. This review focuses mainly on the lipophilicity importance in the environmental and human life sciences, its multidisciplinary character and applications, availability of reliable partition/distribution coefficients and methods of their assessment.

1. Molecular characteristic by lipophilicity – models and stability, and acid–base character. Solubility is usually phrased as the descriptors saturation solubility in a defined solvent at a specified temperature. The definition of stability should be adjusted to the environmental char- Lipophilicity is a physicochemical property of a compound, which acteristics important for the assessment of survival rate of the com- consists of two major structural contributions: a bulk term reflecting pound, whereas acid–base character is determined by a value of loga- cavity formation, hydrophobic and dispersive forces and a polar term rithmic acid dissociation constant (pKa) of the compound [1,3]. reflecting more directional electrostatic interactions and hydrogen The concepts of hydrophobicity and lipophilicity are widely used in bonds. It is generally accepted that the first contribution is called hy- relation to the sorption of organic compounds from water [4]. The drophobicity and the second – polarity. Thus, lipophilicity describes the hydrophobic effect relates to the tendency of non-polar compounds to balance between these two contributions and is measured by the prefer a non-aqueous environment to an aqueous one. The preference of compound's distribution behavior in a biphasic system: a non-polar water to reform an ordered structure creates the driving force for this (organic phase) and a polar (mostly aqueous phase) [1]. According to process. The second concept, lipophilicity, is an extension of the hy- IUPAC definition, lipophilicity is the affinity of a molecule or amoiety drophobic effect and it includes the advantageous solute–solvent in- for a lipophilic environment [2]. teractions that contribute to the distribution of a solute between two On the other hand, lipophilicity is one of the core compound media: water and an organic solvents. Other solubilizing media, such as properties that are required for the estimation of absorption, distribu- biomembranes can also participate in this distribution [1,3,4]. tion, and transport in biological systems, besides the solubility, The models of hydrophobicity or lipophilicity take on a broader

Abbreviations: ABC, ATP binding-cassette; ADME, absorption, distribution, metabolism and excretion; BBB, blood-brain barrier; BCRP, breast cancer resistance protein; CHI, chromatographic hydrophobicity index; CL, clearance; CNS, central nervous system; EKC, electrokinetic chromatography; FMO, flavin-containing monooxygenases; GST, glutathione-S-transferases; HPLC, high-performance liquid chromatography; HSA, human serum albumin; MI, migration index; MP, melting point; MRP, multidrug resistance-associated protein; MS, mass spectrometry; NC, net charge; OCT, organic cation transporter; OAT, organic anion transporter; PBDEs, polybrominated diphenyl ethers; PCBs, polychlorinated biphenyls; PLD, phospholipidosis; QSAR, quantitative structure-activity relationship; QSPkRs, quantitative structure-pharmacokinetic relationships; SFM, shake-flask method; SPME, solid-phase microextraction; SULT, sulfotransferases; TOF-MS, time-of-flight mass spectrometer; TLC, thin-layer chromatography; UGT, UDP-glucuronosyltransferases; VD, volume of distribution ⁎ Corresponding author. E-mail address: [email protected] (T. Chmiel). https://doi.org/10.1016/j.microc.2019.01.030 Received 1 November 2018; Received in revised form 7 December 2018; Accepted 11 January 2019 Available online 14 January 2019 0026-265X/ © 2019 Elsevier B.V. All rights reserved. T. Chmiel et al. Microchemical Journal 146 (2019) 393–406 meaning in chemistry and biochemistry due to the importance of these 2. The role of lipophilicity in the permeation properties of processes in the environment and natural sciences. The hydrophobic xenobiotics effect is regarded to be one of the driving forces for the passive transport of pharmaceuticals through membranes of organisms and as a Lipophilicity influences absorption, distribution, metabolism and component of drug-receptor binding [3,5]. The protein binding, bio- excretion (ADME) processes of xenobiotics affecting their therapeutic distribution and metabolism of drugs may also be modified by their potential and adverse effects (Fig. 2). [10]. Prior to reaching pharma- lipophilicity. It is generally known that the lipophilic compounds are cological target, compound's lipophilicity determines the affinity for a the preferred objects for metabolism and they often lead to high lipophilic environment facilitating its transport through membranes in clearance rates [1,4]. The studies of bioavailability and bioconcentra- a biological system and the formation of complexes between compound tion have attempted to evaluate the extent to which environmentally and receptor binding site [1,17]. relevant chemicals enter the organisms and accumulate in the food chain in relation to compounds lipophilicity [6–8]. The distribution of 2.1. Absorption compounds between water and soil and/or sediment also strongly correlates with the compound's lipophilicity [4] what make possible the 2.1.1. Solubility and lipophilicity descriptors management of hazardous waste disposal, the correct use of crop-pro- Solubility is critical for the absorption and is highly dependent on tecting agents in agriculture and, above all, in environmental risk as- the balance between hydrophobicity and polarity [1,2]. The quantita- sessment. tive descriptor of lipophilicity is logP, which is defined as the ratio of Lipophilicity is characterized by partition coefficient, P orKOW, the concentrations of a neutral compound in octanol and aqueous expressed as logP or logKOW [3,9]. Therefore, the value of logP allows phases under equilibrium conditions [1,9–11] (Eq. 1). to predict the biological activity of chemicals in the body as it describes logP= log ( coct / c wat ) (1) compounds ability to reach its intended target (Fig. 1)[10,11]. The systematic research on lipophilicity was organized by Hansch and Fu- Distribution coefficient (logD) takes into account all forms of a jita who introduced the octanol-water system to model compound's compound: neutral and ionized, present at a given pH [3,18] (Eqs. 2, 3). partitioning into cells [12,13]. Hansch pioneered mathematical logD= logP log( 1+ 10 pH pKa) methods for the correlation studies on the relations between physico- acids (2) chemical properties of molecules and their biological activities, known pKa pH logDbases = logP log( 1+ 10 ) (3) as QSAR investigations [14]. The majority of QSAR models including octanol-water partition coefficient and optimum logP value for the Considering above, the general solubility (logS) equation is ex- compound penetration through biological barriers were established pressed below, where the melting point (MP) describes the lattice en- [12,15]. The development of rapid methods for the lipophilicity as- ergy that is lost on dissolution (Eq. 4)[1,9–11]. sessment such as reversed-phase or biomimetic chromatographic tech- logS= 0. 5 logP 0.01() MP 25 (4) niques allows to establish the lipophilicity libraries [16]. We also observed the deeper insight into the pathway of chemicals from the According the Eqs. 3 and 4 the solubility of an ionizable compound environment to living organism and many new analytical approaches increases exponentially with the difference between pH and pKa [19]. and tools for lipophilic properties analysis. Therefore, we present here In a study by Gleeson, it was found that reducing logP below 3 made the the involvement of these properties into the penetration, metabolism, dependence of solubility on ionization much less significant [20]. The elimination and final environmental fate of chemicals coexisting with variety of parameters related to lipophilicity is presented in Table 1. us. They are commonly used descriptor of the compounds in relation to

Fig. 1. The main areas of lipophilicity application in pharmaceutical and environmental sciences.

394 T. Chmiel et al. Microchemical Journal 146 (2019) 393–406

Fig. 2. Lipophilicity of drugs and other xenobiotics influences their ADME properties and determines their bioavailability and final biological effects.

layer in the brain controls the exchange of drugs, nutrients, hormones, Table 1 Partition coefficients used to evaluate the lipophilic character of compounds. metabolites and immune cells between blood and brain in both direc- tions. The gaps between capillary endothelial cells in most parts of the Symbol Parameter Reference brain are sealed by tight junctions and thus have severely limited per-

logD Octanol-water distribution coefficient [18] meability (Fig. 4)[25]. The majority of xenobiotic BBB penetration is

logKAGP Partition coefficient determined on α1-acid [3] through passive diffusion and generally higher lipophilicity provides glycoprotein based column better central nervous system (CNS) penetration. However, too high logKAO Air-octanol partition coefficient [79] lipophilicity can result in the increased non-specific plasma protein logK Air-soil partition coefficient [62] AS binding [4]. Thus, the highest uptake demonstrates CNS penetrated logKAW Air-water partition coefficient [8]

logKHSA Partition coefficient determined on human serum [3] xenobiotics with moderate lipophilicity values logP/logD from 1.7 to albumin based column 2.8 [25,26]. logKIAM Partition coefficient determined on immobilized [3] artificial membrane column 2.1.4. Skin permeability logKOA Octanol-air partition coefficient [9] The transdermal permeation rate of xenobiotics is limited by the logKOC Organic carbon-water partition coefficient [58]

logKOW, logP Octanol-water partition coefficient [3,9] stratum corneum, which comprises of 10–15 layers of flat keratin-filled logKSA Soil-air partition coefficient [21] cells, closely packed in a nonpolar lipid matrix. A molecule can logKSW Soil-water partition coefficient [21] permeate through the skin via either the transcellular or intercellular logK Water-air partition coefficient [80] WA pathway. The transcellular route requires that the molecule directly logKWS Water-soil partition coefficient [22] logS Solubility [19] passes through both the phospholipid membranes and the cytoplasm of the keratinocytes encountering layers of different lipophilicity. In contrast, compounds crossing the skin by intercellular route must pass through the small spaces between the cells of the skin, making the route their transport inside the living organisms and in the environment more tortuous. This pathway is more common among xenobiotics, [8,9,21,22]. which are usually lipophilic compounds. In contrast, transcellular route is not considered as the preferred way of transdermal transport. This is 2.1.2. Gastrointestinal tract permeability because of low permeability of keratinocytes and the obligation to The majority of xenobiotics including medicines (about 90%) are partition several times from the more hydrophilic keratinocytes to the administered orally, therefore the intestinal epithelial membrane is the lipid intercellular layer [27]. Mathematical models for skin absorption main physiological barrier, which has to be passed by chemicals to of chemicals have been proposed, where lipophilicity, molecular weight enter the bloodstream. This occurs in dependence on the physico- and hydrogen bonding characterize the properties for permeation. The chemical properties and structural characteristics of the compounds maximum skin permeability expressed as optimal logP ranges from 2.5 (Fig. 3). The transcellular and paracellular pathways are dominant to 6.0 [11]. mechanisms and represent the passive transfer by diffusion across the lipid membranes and is the predominant pathway for lipophilic mole- 2.2. Distribution cules [1]. The prevalent models for investigation of intestinal absorption are After the absorption xenobiotics delivered into the living organism Caco-2 cell system and the parallel artificial membrane permeability are specifically transported into various tissues according to individual assay (PAMPA). Different theoretical models for passive membrane tissue characteristics and compound properties. The distribution is de- diffusion have also been derived [17]. There is applied lipophilicity and termined by pH, lipid contents and cell membrane function, that can be polar surface area (PSA) as key descriptors. In these models, the com- expressed by different pattern distribution of acidic and basic compounds with good absorption show logP in the range from −1.0 to 5.9 pounds. and optimal PSA < 131.6 Å2. In general, the increase in lipophilicity Absorbed xenobiotics are reversibly bound to plasma proteins and size reduction (PSA and MW) promote membrane permeability (human serum albumin (HSA), α1-acid glycoprotein (AGP)) and are [1,10]. transported in the bloodstream. Plasma protein binding affects the In case of endogenous compounds, the second transport way is the disposition profile in terms of both clearance (CL) and volume ofdis- active transport, which also occurs across the intestinal epithelial tribution (VD), because only free chemical is available for elimination membranes. However, membrane transporters influence either active and distribution into peripheral tissues [4,10,17]. HSA contains at least uptake or efflux of orally administered chemicals [23]. two different binding sites in the form of hydrophobic pockets and naturally serves as a transporter of a variety of different ligands 2.1.3. Blood-brain barrier [28].Acidic compounds show correspondingly higher binding in com- Most small molecules and virtually all protein and peptide xeno- parison to basic and neutral compounds due to an ion-pair interactions biotics do not cross the blood-brain barrier (BBB) [24]. Endothelial cell with a basic residue within HSA [29]. The correlation between HSA

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Fig. 3. Pathways of introducing xenobiotics into the living organism.

Fig. 4. Schematic representation of blood-brain barrier. binding and logP for numerous biologically active compounds has been 2.3. Metabolic transformations demonstrated with similar affinity for neutral and ionized molecules with acids displaying the greater affinity [30]. Majority of xenobiotics are lipophilic what makes them difficult to The VD is a parameter used to quantify the distribution of a xeno- eliminate. After reaching the liver, as well as in other organs they can biotic between plasma and the rest of the body [10]. This parameter, be subjected to metabolic transformations. This process aims to increase along with CL allows for the determination of the half-life of a drug and hydrophilicity making the foreign compound easily excreted via bile thus influences dosing interval. Ionization state has the most dramatic and urine. Although metabolism is generally a detoxication process, in effect on the VD. Basic molecules have the highest VD values whereas some cases the reactive intermediates may be formed which are much acidic molecules the lowest. The reason for that is higher plasma pro- more toxic than the parent compound. Xenobiotics may undergo one or tein binding for acidic compounds and the tendency of basic com- two phases of metabolism. In phase I a polar reactive group is in- pounds to interact with phospholipid membranes [20]. Lipophilicity is troduced into the molecule mainly with the participation of cytochrome particularly important for the distribution of a drug in vivo. The in- P450 isoenzymes (P450) and to a lesser extent of flavin-containing creasing of logP will generally lead to an increase in the VD of neutral monooxygenases (FMO) and hydrolases. Then, phase II conjugating and basic compounds in the body, whereas this effect has not been seen enzymes such as UDP-glucuronosyltransferases (UGT), sulfotransferases for acids and zwitterions [31]. (SULT) and glutathione-S-transferases (GST) introduce much more

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Fig. 5. The level of lipophilicity after xenobiotic metabolism. bulky substituents, such as sugars, sulphates, or amino acids which phase metabolism. Owing to high solubility in water, hydrophilic spe- cause a significant increase in water solubility of the compound (Fig. 5) cies generally can be excreted outside the body through urine without [32]. Generally, the binding sites of xenobiotic metabolizing enzymes chemical modification [34]. Drug and toxicant transporters are ex- are lipophilic in nature and hence more readily accept lipophilic mo- pressed in a variety of organs including liver, intestine, kidney and lecules, as it was described for P450. Depending on P450 isoenzyme, brain. ATP binding-cassette (ABC), transporters localized on the cana- the average logP of their substrates ranges from 1.1 to 3.7. Metabolic licular membrane of hepatocytes, such as P-glycoprotein, multidrug stability of a compound in relation to lipophilicity can be improved in resistance-associated protein (MRP) 2 and breast cancer resistance phase II transformations by the introduction of substituents with low protein (BCRP) is the major family of proteins responsible for the ex- lipophilicity or isosteric atoms/functional groups, which imparts in- cretion of drugs into the bile. Renal reabsorption and excretion are creased polarity to the molecule [33]. mediated by organic cation transporter (OCT) 2, organic anion transporters (OAT) 1 and 3 situated on the basolateral side of renal proximal 2.4. Elimination and clearance tubule cells as well as by MRP1 and MRP2 localized on the apical side (Fig. 5)[35]. These membrane transporters involved in xenobiotic ab- Phase I and II metabolites and in some cases unchanged xenobiotics sorption, disposition and excretion can be major determinants of the are excreted by membrane efflux transporters in the process called III pharmacokinetic, safety and efficacy profiles of chemicals that have

397 T. Chmiel et al. Microchemical Journal 146 (2019) 393–406 penetrated living organism [36]. metabolism with all enzymes of I and II phase described in Section 2.3 The key measure of xenobiotic elimination is the CL, which may be and thus the physicochemical properties such as size or mass, charge defined as the theoretical volume of fluid from which chemicals are and lipophilicity can be affected [7,42,45]. As a consequence, it may completely removed in a given period of time by the eliminating organ. have impact on their solubility, ability to cross and interact with bio- The kidney and liver serve as the major organs responsible for the re- logical membranes, as well as on the rate of excretion and half-life in moval of xenobiotics [35]. Renal elimination of very polar compounds plasma. Due to the complex nature of health-promoting compounds in can contribute to a significant proportion of the total CL, whereas more food as well as different mechanism of absorption and metabolic lipophilic compounds are efficiently reabsorbed in the kidney tubule transformations of hydrophilic and lipophilic bioactive compounds and tend to undergo metabolism, which results in less lipophilicity [42], the lipophilicity indices including partition coefficients on bio- [35,37]. Studies on intravenous pharmacokinetic parameters in humans mimetic stationary phases (KIAM,KHSA,KAGP; defined in Table 1) and for the sets of xenobiotics exhibited rather weak but statistically sig- KOW are useful tools in assessment of their biological activity [43–45]. nificant nonlinear relationship between logP and the in vivo CL [20]. The knowledge of these various lipophilicity descriptors allows to estimate food components permeability through cell membranes, binding 3. Lipophilicity in pathological response capacity with plasma proteins and their bioavailability. Therefore, the lipophilic characteristics of food-derived compounds can help to better In addition to described above ADME parameters, lipophilicity is understand their fate in the human body, to build models for biological also one of the key factors determining compound binding affinity to partition processes and to predict in vivo distribution of potential target proteins, which are responsible for the final biological effect. The bioactive molecules (i.e. nutraceuticals) [3,12,42,44]. Improving the analysis of drug affinity to a given molecular target indicates that uptake of highly lipophilic bioactive compounds through design food- within oral drugs, different target classes have significantly different based delivery systems can also be supported by lipophilicity studies of average logP value [3]. The investigation of the relationship between functional food ingredients [6]. target class and the physicochemical properties of ligands revealed distinct differences in the distribution of lipophilic properties between 5. The impact of lipophilicity on environmental fate of sets of compounds active against different target gene families. For compounds example, ligands for the nuclear hormone receptors are the most lipophilic and generally more lipophilic compounds within a series will be Chemicals released into environment can occur far away from the more potent against their target. Thus, medicinal chemistry optimiza- release point and have rather unexpected effects [46], for instance, tion needs to be balanced and multidimensional [3,38]. freons get to the stratosphere and contribute to the disappearance of Xenobiotic ability to act with multiple molecular targets and to ozone layer [47], polychlorinated biphenyls (PCBs) were detected in exhibit distinct physiological effects is called “promiscuity”. In general, Norwegian fish [48] organochlorinated pesticides were found in polar more lipophilic molecules are less selective and have greater ability to bear bones [49] and trichloroethylene was present in groundwater bind to any target and unwanted effects leading to toxicity can be [50]. Therefore, tools to predict chemicals' fate are of crucial im- predicted [4]. Evidence for increased “promiscuity” with high lipo- portance (Fig. 6). philicity was provided by analysis of a set of 2133 compounds. There The contaminants' movement through ecosystems is controlled by was shown that this property increased dramatically for logP > 3 and two factors: physicochemical properties of individual compound and was controlled also by ionization state. Bases and quaternary bases characteristic of various compartments of natural environment. were notably more promiscuous than acids, neutral compounds or Therefore, the partitioning of these compounds through sediment, zwitterions [38]. water or air depends on their molecular size, polarity and structure. The Xenobiotic-induced phospholipidosis (PLD) is characterized by in- most important property is solubility in water, because it may impact tracellular accumulation of phospholipids with lamellar bodies, most on sorption processes in soil and volatility of compounds from water likely from an impaired phospholipid metabolism of the lysosome. environment, as well as affect transformations by hydrolysis, photo- Organs affected by PLD exhibit inflammatory reactions and histo- lysis, biodegradation, oxidation and reduction. Solubility also influ- pathological changes. Most drugs that induce PLD are cationic amphi- ences washout chemicals from atmosphere by rain [51,52]. The prop- philic compounds and share similar structural features - a hydrophobic erties of compound affect partition coefficient values that allowto ring structure and a hydrophilic side chain with a basic amine [39]. define the contaminants' ability to exchange between different en- According to Ploemen et al. compounds are predicted to be PLD in- vironmental compartment and their preferred accumulation media ducers when [(pKa)2 + (logP)2] > 90, provided that most basic [53]. Partition coefficients related to soil, water and air environment pKa > 8 and logP > 1 [40] whereas PLD is considered positive for the are summarized in Table 1. The values of these coefficients for chemical compounds with a net charge (NC) in the range of 1 ≤ NC ≤ 2 and a compounds are mainly determined using the standard testing guidelines logP > 1. Furthermore, combining VD with pKa of the most basic (e.g. the Organization for Economic Cooperation and Development group and logP provides greater concordance in predicting PLD [41]. (OECD) guideline) and other empirical methods [54]. Examples of such methods for the most important partitioning processes in the environ- 4. Lipophilicity in bioavailability of food components ment are summarized and briefly discussed in Table 2. However, due to the time-consuming, laborious and relatively high costs of experimental In general, bioactive food components, whether derived from plant determinations, partition coefficients are more often estimated by or animal sources, are released from food matrix, solubilized, trans- computation methods applying different algorithms based on struc- ported and absorbed within the human gastrointestinal tract (see p. tural, atomistic, topological, electrotopological, or other considerations 2.1.2). After digestion process, they are secreted into the lymph, me- on a drawn chemical structure. Recently, the calculation methods based tabolized and then may reach their place of action. The biological ef- on solvation free energy, such as the conductor-like screening model for fects of food components are highly dependent on the chemical form of real solvents (COSMO-RS) and the polarizable continuum model (PCM), the compound/element and its bioavailability [6,42]. Anyway, for the have been developed and applied for prediction of compounds partition dietary bioactive compounds including vitamins, macro- and micro- between various environmental compartments. A detailed description nutrients, carotenoids, phytosterols, polyunsaturated fatty acids, fla- of these methods has been presented by Mackay et al. [55]. vonoids and other polyphenols, to reach their target site, the crucial The transfer between the atmosphere and water reservoirs is one of step is absorption which is largely governed by lipophilicity and degree the key processes that affects transport of many organic compounds in of ionization [43,44]. Moreover, the absorbed food compounds undergo the environment. One of important physicochemical parameters that

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Fig. 6. Environmental fate of chemical compounds. The abbreviations refer to the lipophilicity descriptors (partition coefficients) defined in Table 1. describes this mobility is Henry's Law constant (H), which is a ratio of body may also migrate to cub's tissue. For instance, in case of mammals, vapor pressure substance above a solution (ps) to its aqueous solubility it is possible to transfer lipophilic compounds from adipose tissue to (S) (Eq. 5)[56]. milk that contains high level of lipids. For this reason, cubs are exposed H= p/S[Pa·m·mol3 1 ] to these chemicals during the feeding. Moreover, this exposure has al- s (5) ready begun in fetal period. The small size of fed cubs causes that even In atmospheric chemistry, Henry's Law constants are classified into temporary exposure can lead to much higher levels of xenobiotics in two types: ‘Henry's Law solubility constant’ and ‘Henry's Law volatility their blood and tissues than in the mother's body [63]. constant’ (KAW). Both types are needed to explain distribution of com- The harmfulness of xenobiotics to offspring can be determined by pounds between the air and aerosol particles or liquid cloud droplets. evaluation of health risk. Its purpose is to accurately determine and Furthermore, in other environmental research areas, these constants are assess all possible risks associated with exposure and even to help in necessary to evaluate the vaporization of pollutants during wastewater finding a way to reduce the exposure. The health risk assessment pro- treatment processes or from environmental waters [56,57]. cess includes four main steps: hazard identification, dose-response as- The transport of compounds between air and soil is another im- sessment, exposure assessment, and risk estimation and characteriza- portant process determining the environmental fate and human ex- tion. To realize each step a lot of data can be used, obtained by posure. The main processes occurring in this exchange are dry deposi- epidemiological investigations, laboratory animal tests or computer tion (association with particles, vapor adsorption), wet deposition modeling, where various partition coefficients are taken into con- (disposal of vapor- and particle-sorbed compounds) and volatilization sideration [62]. from the soil. Soil is fundamental reservoir for chemicals in the ter- It is suspected that the expression of lipophilic nature of the com- restrial environment. However, the removal processes, such as leaching pound can be significant for estimation of efficiency of their removal to groundwater, biodegradation or migration to atmosphere also occur during treatment processes as well as for the prediction of wastewater [9,46]. To describe the pathway of compounds found in soil, various treatment efficiency models. Contaminants elimination by sorption to coefficients related toKOW are used: KOA,KAO,KOC,KSA,KAS,KWS and suspended materials (solids, colloids, and some others), occurs during KSW (see Table 1 and Fig. 6)[21,54,58]. primary and secondary wastewater treatment stage (sedimentation, An exposure pathway is only operative when the compound can coagulation and/or flocculation). This process is not significant for pass from an environment to a living organism under different path- compounds exhibiting logKOW < 2.5, whereas moderate and high ways: bioaccumulation, bioconcentration and biomagnification. sorption may be observed for chemicals with logKOW 2.5–4.0 and > Bioaccumulation refers to the accumulation of contaminants in living 4.0, respectively [64,65]. organism and occurs when an organism absorbs a toxic substance from the environment at a rate greater than that, at which the substance is 6. QSAR in permeation of xenobiotics and environmental fate lost. Bioconcentration describes the uptake and accumulation of a assessment substance from water alone, whereas biomagnification is defined as durative increase of substance concentration in organism together with It is now clearly recognized that a successful drug candidate re- increasing trophic position within food chain [59]. In this three cases, quires not only potency and selectivity, but also a suitable pharmaco-

KOW is a useful index for assessment of the potential of substance mi- kinetic profile [66]. The studies showed that less lipophilic compounds gration from water residues, soils and among food chain. It has been are developed easier during preclinical and clinical investigations, im- estimated that bioaccumulation occurs for chemicals with KOW > 2000 plying the role of lipophilicity in QSAR approach [67]. The majority of (logKOW > 3.3), whereas easily bioaccumulative compounds with a QSAR models includes lipophilicity expressed as logP [68] as it is one of tendency to biomagnification at different trophic levels exhibit the major factors in research aimed at rational design of new ther- logKOW > 5 [59–62]. Lipophilic compounds are accumulated in the apeutic agents [4]. adipose tissue of organisms where they can have long elimination To express the probability of a compound to become a pharma- period. Furthermore, lipophilic xenobiotics that accumulate in female's ceutical drug the term drug-ability is used. Among a lot of approaches

399 .Cme tal. et Chmiel T. Table 2 Experimental methods for determining one of the crucial partition coefficients in environmental processes.

Type of partition Method of determination Comments Application Ref. coefficient

KAW Gas stripping method very low KAW values are difficult to assess, especially if the solute is polar or surface polybrominated diphenyl ethers (PBDEs), PCBs, mercaptans, dimethyl [81–83] • active, sulfide very long stripping time may be needed, • aerosol particles of water should be avoided if the air-phase concentration is • measured Equilibrium partitioning in closed • less time-consuming if the compounds are volatile, benzene derivatives, chloroorganic compounds, isopropyl alcohol, [84,85] systems (EPICS) the combination of the EPICS technique with SPME allows to measure KAW in a wider acetone, methylacrolein, methyl vinyl ketone • range of 0.0023–13.5, free of equilibration problems, • removal of a vapor-phase headspace sample from the closed vessel used for • equilibration and its subsequent analysis is required, • no mass transfer limitations during the experiment, • simple apparatus required KOA Generator column/fugacity meter • direct measurement of KOA , chlorinated benzenes, PCBs, polychlorinated naphthalenes, PDBEs, [77,86] technique • time-consuming, in particular at low temperatures and for low volatile compounds, dibenzo-p-dioxins and dibenzofurans, organochlorine pesticides • complex multi-step procedure, • requires quantitative analysis (calibration) Gas chromatographic retention time • simple and time-saving (relatively rapid), organophosphate flame retardants, PCBs, PBDEs, polycyclic aromatic [86–88] (GC-RT) method • recommended for low volatile compounds hydrocarbons, polychlorinated benzenes, biphenyls and naphtalens • indirect method that required sufficient number of calibration compounds KOC Batch equilibrium method time-consuming, laborious and very expensive, volatile methylsiloxanes, pesticides, organophosphate esters [89–92] • evaluation of the adsorption of chemicals on different soil types, • in some cases more tedious direct analysis of soil, involving stepwise soil extraction is 400 • required (i.e. adsorption of the analyte on surfaces of the test vessels, instability of the analyte during test, weak adsorption giving only small concentration change in the solution), problems with analytes characterized by low water solubility (< 0,1 mg/L) and • highly charged substances, soil types for adsorption/desorption experiments should be selected and prepared in • appropriate way, selection of optimal soil/solution ratios is required High performance liquid • rapid screening method, pesticides, triazines, amides, polycyclic aromatic hydrocarbons, PCBs, [93–96] chromatography (HPLC) method • high reliability of the method, especially in comparison with computation methods, alcohols, halogenated benzenes and phenols, benzenonitriles • tests performed on HPLC columns with cyanopropyl stationary phase (dual-nature of • stationary phase), real soils can be used as packing material of HPLC column (soil column LC), • method cannot fully replace batch equilibrium method, • useful for chemicals which are difficult to study in other experimental systems (i.e. • volatile substances; substances which are not soluble in water at a concentration which can be measured analytically; substances with a high affinity to the surface of Microchemical Journal146(2019)393–406 incubation systems), • convenient and low-cost method T. Chmiel et al. Microchemical Journal 146 (2019) 393–406

from a set of descriptors, may give the considerable insight into the control of physicochemical and biological properties of each compound [74]. In environmental chemistry, QSPR models are mainly used to estimate partition coefficients of compounds between various elements of the environment [9,54,77]. Presently, the major goal is to improve the interpretation of the models and their predictive power in a wide range of chromatographic systems. For instance, QSAR studies ex- panded also into quantitative structure-pharmacokinetic relationships (QSPkRs) [17]. Furthermore, the studies of the lipophilic properties have revealed a wealth of information on intermolecular forces, in- tramolecular interactions, and specific elements of molecular structure [76,78].

7. Concluding remarks

The understanding of lipophilic properties of the compound allows either to predict the routes of its transport in a variety of biological Fig. 7. Molecular properties associated with xenobiotic permeability presented systems including plant and animal organism or to propose the models as Lipinski's rule of five [5]. of pollutant transport and its accumulation in ecosystem. We demonstrate here that the solubility and lipophilicity descriptors define not only the permeability potency of xenobiotics or their dis- Lipinski proposed a way to assess whether a chemical compound of a tribution profile, but also answer in respect to their potency tometa- certain biological activity has a chance to be an active therapeutic after bolic transformation. Higher lipophilicity, for example, promote phase I oral administration [5]. Lipinski's rule known as the ‘rule of five’ of metabolism of chemicals, whereas products of this transformation (Fig. 7) describes the molecular properties that are associated with drug are good substrates for phase II of transformation giving the polar solubility and permeability. These parameters are crucial for ADME as substrates suitable for membrane efflux transporters in phase IIIof well as for its pharmacodynamic and toxicological profile. Accordingly, metabolism. Lipophilicity is also the key factor determining the ability Gleeson suggested that compounds with logP < 4 stand a much higher of the compound to bind to the target proteins, what is responsible for chance of success against a comprehensive set of ADME parameters the selective activity or pathological response. Moreover, the optimal [20]. value of lipophilicity descriptor is a preliminary condition for finding Optimum region of lipophilicity for therapeutic agents is proposed the optimal structure of a potent drug in QSAR studies. Lipophilicity within a narrow range of logP 1–3 [38]. However, to be a successful plays an important role in estimating bioaccumulation in animals and drug candidate, a compound should have a balance of lipophilic and plants, predicting adsorption in soil and sediments, and, above all, in hydrophilic properties. The lipophilicity of a potent drug should be: the evaluation of health risk of emerging environmental exposures. Lipophilic properties modulated by the degree of ionization also govern 1) high enough to enable adequate permeability through biological the food delivery systems of bioactive compounds. As a result of mul- membranes and to allow binding to molecular target, tidisciplinary applications, the determination of various partition 2) low enough to enable solubility in aqueous environment and to coefficients as a measure of lipophilicity has now become almost anart, prevent undesired drug features. and thus different experimental methods of lipophilicity assessment are still being developed, especially towards providing a fully validate and Optimal lipophilicity allows to avoid the extensive metabolism, high standardized high-throughput procedures. plasma protein binding, off-target activity or accumulation to tissues. It In our opinion the future trends in scientific areas focusing on the is strongly suggested, that the control of drug candidate logP value lipophilic properties of chemical compounds as a key aspect will in- within indicated range is crucial for ultimate success in drug develop- clude the following efforts. First, the improvement of existing experiment [68]. mental methods for determination of partition coefficients. Second, the There is a wide range of chromatographic methods for the de- elaboration of novel approaches that provide reliable and reproducible scription of potent therapeutics in the field of their lipophilic proper- results in a wide range of lipophilicity, especially for new type of che- ties. They include various reversed phase liquid chromatography ap- micals released to the environment or proposed as potential bioactive proaches such as: (i) thin-layer chromatography [69], (ii) high- ingredients of pharmaceuticals. There is also a question: should there be performance liquid chromatography (HPLC) in isocratic mode [70], attempts to unify the parameters defining lipophilicity, e.g. one uni- (iii) gradient HPLC [71], as well as the double gradient methods (i.e. versal partition coefficient for a given purpose? On the other hand, pH/methanol gradient) [72], which have been developed and applied future prospects in design of new biomimetic HPLC stationary phases by a lot of research groups, including Kaliszan et al. [71,73]. Chro- may result in introduction of new lipophilicity descriptors, such as matographic methods, in contrast to direct partition coefficient ex- various tissue/plasma or tissue/blood partition coefficients. These types periments, allowed for faster and easier determination and for the of data can be used to develop more sophisticated physiologically-based comparison of lipophilic properties for large number of xenobiotics models that can describe full pharmacokinetic profile of the substance. [74]. The detailed comparison of various analytical methods for lipo- Therefore, the tendency to unify the lipophilicity parameters is deba- philicity assessment is presented in Table 3. table and depends on the type of partition and distribution processes. QSAR models with a variety of lipophilicity descriptors have been The next future trend could be to develop valid, low cost and fast developed for various types of biological, pharmaceutical and en- computation methods (e.g. “first-principles” approaches that based only vironmental purposes [68,73,75]. Following the expansion of lipophi- on a few optimized, general parameters and do not require experi- licity descriptors a lot of new forms of QSAR approach have been es- mental data) and apply them for estimation of lipophilicity of not well- tablished. The designation of structure-activity (SA) in QSAR has been characterized chemicals and complex samples. This approach needs the substituted for example by structure-property (SP) or structure-reten- application of chemometric tools to extract the meaningful and inter- tion (SR) [76]. There is widely recognized that the QSAR, QSPR or pretable features from the multivariate HPLC raw data and then may QSRR relations presented in Fig. 8, obtained in purely empirical fashion provide new highly descriptive lipophilicity indices to build databases

401 .Cme tal. et Chmiel T. Table 3 Methods for determination of lipophilicity of chemical compounds.

Method Advantages Disadvantages Applicability Lipophilicity Ref. descriptor

Direct methods Shake-flask method (SFM) simple, reliable, the most realistic method correlated time-consuming, labor-intensive, high solvent medium hydrophilic or lipophilic logP [17] well with partitioning phenomenon, various partition consumption, requires a large amount (10–50 mg) of compounds that do not dissociate under the solvents high purity compounds, emulsion formation (mainly assay conditions (neutral form); for hydrophobic compounds), impact of relative −3 < logP < 4 solubility, adsorption onto vessel walls, sensitivity to impurities, concentration dependent Miniaturized SFM simple, rapid, high-throughput, reliable and the most high purity of compounds required, emulsion compounds in a neutral form logP [97] realistic method, various partition solvents, potential formation (mainly for highly hydrophobic (undissociated), extended range of for full automation compounds), impact of relative solubility, sensitivity to lipophilicity compared to the traditional impurities SFM; −2 < logP < 6 Slow-stirring method simple and reliable method, problem of emulsion time-consuming, labor-intensive, expensive, relatively compounds in a neutral form logP [9,98] formation is eliminated, various partition solvents large amount of pure compounds used, concentration (undissociated) with different lipophilicity, dependent, solvent consumption especially hydrophobic compounds with logP > 5 Filter probe method simple, partially automated and rapid, well adapted to contamination of aqueous phase by octanol is lipophilic compounds in a neutral and logP or logD [17,99] determine the logD profile as a function ofpH problematic for hydrophobic compounds (prevention dissociated form (ionic substances); by using the water-plug aspiration/injection method), logP > 0.2 time-consuming set up, expensive equipment

Chromatographic methods Thin-layer chromatography (TLC) simple, rapid, cheap, small amount of analyte detection requires visualization reagents (post- moderately and highly lipophilic RM,RMw ,S [69] required, simultaneous analysis of several compounds, chromatographic derivatization) or specific properties compounds; 4 < logP

402 does not require quantitative analysis, low of the compounds (i.e. UV absorption, fluorescence), consumption of organic solvents (environmental problems with repeatable analysis conditions that can friendly method) be solved by using fully automated TLC system (higher equipment costs) Classical HPLC in isocratic mode relatively cheap, fully automated, small amount of different retention mechanisms, possible interactions moderately and highly lipophilic logk, logkw, S, CHI [100] analyte required, on-line detection, does not require with the surface of stationary phase, time-consuming compounds in a neutral and dissociated (φ0), logP or logD quantitative analysis, independence of measurements in some cases, solvent consumption, calibration set form; 0 < logP < 8 from low compound solubility and impurities or necessary, limited pH range for some silane based degradation products reversed-phase columns (alternative: polymer-based columns, columns with hybrid organic-inorganic silica or based on bidentate technology are stable over a wide pH range) Gradient HPLC fast, fully automated, high-throughput, small amount relatively expensive equipment for LC-MS based compounds with wide range of lipophilicity CHI (φ0), kg, logP or [71,99,100] of analyte required, on-line detection, does not require approach (costs of detector, especially TOF-MS), in a neutral and dissociated form; logD quantitative analysis, independence of measurements calibration set necessary −3 < logP < 8 from low compound solubility and impurities or degradation products, relatively low consumption of

organic solvents, results correlate well with SFM, Microchemical Journal146(2019)393–406 simultaneous analysis of dozens compounds (possible using MS detection and fast gradient), useful for inter- laboratory study – good reproducibility (mainly results in CHI scale), simultaneous determination of logkw and pKa using double pH/methanol gradient method (additionally high screening rate of ~100 compounds/ day), allows to create profiles of logD = f(pH) (continued on next page) .Cme tal. et Chmiel T. Table 3 (continued)

Method Advantages Disadvantages Applicability Lipophilicity Ref. descriptor

Biomimetic liquid chromatography rapid (mainly fast gradient methods used), fully high cost of the biomimetic columns with immobilized moderately and highly lipophilic logk, logkw, S, CHI [3] automated, high-throughput, on-line detection, does biomolecules (i.e. plasma proteins, membrane lipids, compounds in a neutral and dissociated (φ0), kg, logP or logD not require quantitative analysis, independence of liposomes, etc.), column lifetime, pH range limited to form; 0 < logP < 8 measurements from low compound solubility and 2.5–7.5 (for longer lifetime of some columns the range impurities or degradation products, relatively low of 7.0–7.5 is even recommended), calibration set consumption of organic solvents, useful for inter- necessary laboratory study (mainly results in CHI scale), simulates well biological partition processes and correlates with pharmacokinetic parameters Electrokinetic chromatography rapid, cheap, high-throughput, small amount of poor reproducibility in case of vesicular EKC, moderately and highly lipophilic logk, MI, logP [101] approaches (micellar, analyte required, insensitivity to samples impurities, determination of solvation parameter model required compounds in a neutral form microemulsion or vesicular EKC) wide dynamic range, working in full pH range, (undissociated); −1 < log P < 7 possibility of automation

Other methods Potentiometric titration (pH-metric rapid, working in wide pH range (1.8–12.2), well requires a large amount of pure compounds (2–50 mg), ionizable and soluble compounds with wide logD, logPN, logPI [102] method) adapted to determine the logD profile as a function of relatively expensive equipment range of lipophilicity; pH, independent of the magnitude of logP, various −1 < logP < 8 partition solvents Cyclic voltammetry working in full pH range, results independent of the limited number of solvent systems used, relatively low lipophilic and mainly hydrophilic logPo,i [103] experimental conditions large amount of sample required (1–10 mg) compounds only in dissociated form (ionic compounds); −8 < logP < 1 SPME-based approach simple, small amount of analyte required, possibility of limited lifetime of fiber coatings (stationary phase), moderately and highly lipophilic logK [104] automation, good correlation with SFM results, results dependent on experimental conditions compounds in a neutral and dissociated

403 solventless extraction (environmental friendly form; 0 < logP < 5 method)

Abbreviations: CHI(φ0) – chromatographic hydrophobicity index; k – retention factor; kg – apparent capacity factor; kw – retention factor extrapolated to pure water as a mobile phase; K – distribution constant of analyte partitioning between the aqueous and stationary phase; MI – migration index; MS – mass spectrometry; PI – partition coefficient of ion pairs;N P – partition coefficient of neutral species,0,I P – standard partition coefficient of ion species; RM – retardation parameter; RMw – retardation parameter for pure water as a mobile phase; S – regression slope (directly linked to specific surface area of stationary phase); SPME – solid-phase microextraction; TOF-MS – time-of-flight mass spectrometer. Microchemical Journal146(2019)393–406 T. Chmiel et al. Microchemical Journal 146 (2019) 393–406

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