Efectos de los cálculos aplicados al índice de consumo de materia prima en la

Table 4.2 gives a brief description of the significant molecular descriptors used in the models. For the sake of this discussion, the descriptors in this work can be classified roughly into five categories as follows: lipophilicity, ionisation, molecular size and topological and constitutional descriptors.

It can be seen in Table 4.2 that lipophilicity descriptors such as log D at different pH levels and surface area of hydrophilic molecules (SlogP_VSA0) are present in all models. In all interpretable models (except for the linear regression equation), lipophilicity descriptors show a negative effect on the biliary excretion of compounds. This may relate to the fact that highly lipophilic compounds are known to be highly extracted and metabolised in the liver (Proost et al., 1997) rather than being excreted unchanged through bile or kidney. For example, metabolism by

cytochrome P450 enzymes (Lewis and Ito, 2010) and (UDP)-

glucuronosyltransferase (Smith et al., 2003) is mainly controlled by lipophilicity and increased for more lipophilic compounds. There have been inconsistent findings in the literature regarding the effect of lipophilicity on the biliary excretion

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of xenobiotics. Proost et al. found no significant correlation between lipophilicity and biliary excretion of a series of bulky organic cations despite it being the predominant factor for the degree of plasma protein binding and hepatic uptake rate (Proost et al., 1997). Similar observations have been made for other compilations of biliary excretion data (Yang et al., 2009). Other studies indicate negative effect of lipophilicity on the biliary excretion within the range of compounds studied (Luo et

al., 2010; Varma et al., 2012). Lipophilicity has been associated with many models

of ADME properties (Hansch et al., 2004). It is a well-established fact that compounds with higher logP have poor aqueous solubility and are more likely to pass through lipid bilayer of biological membranes (Kerns and Di, 2008). The general trend in the literature with regards to the role of lipophilicity in pharmacokinetic processes indicates that more lipophilic compounds have higher oral absorption, plasma protein binding, and volume of distribution (van de Waterbeemd et al., 2001; Obach et al., 2008; Newby et al., 2013b) and are more prone to P450 metabolism (Lewis and Ito, 2010; van de Waterbeemd et al., 2001). This may lead to the reduced chance of excretion through bile as the intact drug. All models presented in this work indicate the significant role of ionisation and polarity through molecular descriptors such as COOH, fU, FCASA− and SddssS_acnt. Acids are able to ionise into anions which are substrates of several transporters (generally organic anion transporters). Compounds that carry positive as well as negative charge or partial charges can use both the ‘organic anion’ and the ‘organic cation’ transport systems (Koepsell et al., 2001). For example, OAT3 accepts various kinds of bulky hydrophobic anions, while OAT1 can transport relatively hydrophilic small molecules, such as nucleoside analogues (Maeda et al., 2010). Besides, monocarboxylate transporters (MCT1 to MCT14) constitute a family of proton-linked plasma membrane transporters that carry molecules having one carboxylate group. MCT1 is expressed nearly all over in every tissue in the human body and also in rat and calves hepatocytes (Kirat et al., 2007). MCT2 is abundant on the surface of human, rat and hamster hepatocytes (Halestrap and Meredith, 2004). MCT5 and MCT8 are also known to play transporting role in rat hepatocytes (Halestrap and Meredith, 2004). Studies of biliary excretion of exogenous compounds have indicated the relation between polarity and biliary excretion stating that possession of a strongly polar anionic group was important

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factor in appreciable biliary excretion (Luo et al., 2010; Millburn et al., 1967). In all the interpretable models reported here, polarity descriptors show a positive impact on biliary excretion. Examples are the positive coefficients of dipole moment (AM1_dipole) in the linear regression equation and higher percent of compounds with lower unionised fractions at pH 7.4 (fU) in RT (1).

Molecular size is the other important factor in biliary excretion represented in the models by molecular descriptors such as kappa shape indexes, hydrophobic volumes (vsurf_W1 and vsurf_W3) and surface areas of atoms with specific charge or lipophilicity ranges (e.g. PEOE_VSA_NEG and PEOE_VSA_HYD). These molecular descriptors show positive effect on biliary excretion level in all models. This is in line with the common understanding that a molecular weight threshold may apply to biliary excretion of compounds, and that high molecular weight compounds may be predominantly excreted through bile (Yang et al., 2009; Varma

et al., 2012; Millburn et al., 1967). Yang et al. (Yang et al., 2009) suggested a

molecular weight threshold value of 400 Da for biliary excretion of anionic drugs in rats using 164 drugs. In this study, regression tree analysis found the threshold value for molecular weight to be at 347.9 Da for biliary excretion in rat (I-tree (1)). Incidentally, this regression tree had the second highest prediction accuracy for the external validation set amongst the RT models. This was despite the fact that molecular weight was not the descriptor of choice by C&RT analysis.

The incorporation of some structural fragments in the models gave interesting information regarding molecular requirements for biliary excretion. Examples include SddssS_acnt and SsssCH which indicate higher biliary excretion of compounds containing sulphate groups and non-branched structure (MLR). Compounds containing carboxylic acid groups are also more likely candidates for biliary excretion according to I-tree (2). Up to half of compounds in our dataset contain –COOH groups (103 compounds out of 217). Sixty-five out of 103 COOH containing compounds had biliary excretion of > 20%. Varma et al. (Varma et al., 2012) have analysed the interconnection between physicochemical requirements of OATP substrates and the biliary excretion rates. It was then suggested that substrate specificity of OATPs including acidity may primarily indicate the elimination through bile (Varma et al., 2012).

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