haem iron 77 haemolysis 112 haemolytic anaemia 107 half-life 17, 20, 24, 33 dosing interval 20 clearance 20 volume of distribution 20 halofantrine 37 haloperidol 28

H-bonding 39, 40, 45, 48, 60, 136 hepatic blood flow 129 hepatic clearance 60, 130 hepatic extraction 19, 23

blood flow 19 hepatic impairment 56 hepatic microsomes 128 hepatic necrosis 103 hepatic portal vein 22 hepatic shunts 56 hepatic uptake 60, 61, 131 hepatitis 104 hepatocyte 60, 129, 138 hepatotoxicity 102, 105 high throughput permeability assessment 137 high throughput screening 133

high-speed chemistry 134 HT-29 44 human exposure 99 hydrogen abstraction 80 hydrogen bonding 6 hydrophilic compounds 51 hydrophobicity 2 hydroxylamines 91, 111 hyperkeratosis 106 hypersensitivity 112

i idiosyncratic 118

iminium ion 110, 111

immobilized artifical membranes 136

immune response 102

in silico 135, 137

indinavir 37

indomethacin 105

interstitial fluid 47

intracellular targets 47

intravenous infusion 20, 88

intrinsic clearance 128

iodine 101

ion-pair interactions 52 isolated perfused rat liver 61 isoprenaline 91

k ketoconazole 37, 61, 71 kidney 62, 100

l lidocaine 109 ligandin 48 lipid-bilayer 37

lipophilicity 2, 36, 43, 48, 63, 102, 136, 138 calculation approaches 136 fragmental approaches 136 measured 136 liposome/water partitioning 136 liquid chromatography/mass spectro-metry 137 liver 56 local action 89 lofentanil 30 log D 4, 39, 45, 48, 49 log D7.4 63, 69 log P 2, 6 bonding 6 hydrogen 6 molar volume 6 polarity 6

size 6

loop diuretics 100

loop of Henle 67

low solubility 37

m macrolide 54

maximum absorbable dose 45 maximum life span potential 128 MDCK 44 melanin 48 membrane barriers 2

phospholipid bilayers 2 membrane interactions 48 membrane permeability 136 membrane transfer 65 membrane transport 137 membrane 37 MetabolExpert 138 metabolic clearance 63 metabolic lability 39 metabolism 65, 75, 137, 138 conjugative 75 oxidative 75 phase I 75 phase II 75 metabolite 138 MetaFore 138 metazosin 127 Meteor 138

methaemoglobinemia 112 methyl transferase 92 metiamide 114 metoprolol 42, 51, 79 mianserin 110 microdialysis 50 microsomal stability 129 midazolam 23, 82, 124 minoxidil 95

molecular lipophilicity potential 10 molecular modelling 138 molecular size 45, 48 molecular surface area 8 absorption 8 bile excretion 8 molecular weight 43 moricizine 118 morphine 91, 95 myeloperoxidase 106 myosin 48

n napsagatran 131 N-dealkylation 82, 111

N-demethylation 82, 84 necrosis 102 nephron 67

neural network 115, 136, 138 nifedipine 53, 54 nitrenium ion 109, 119 nitrofurantoin 37 NMR spectroscopy 137 no-effect doses 100 nomifensine 107 non-linearity 137

non-steroidal anti-inflammatory drugs 80 nucleophilicity 91

o occupancy theory 25 octanol 5, 8

alternative lipophilicity scales 8 H-bonding 5

model of a biological membrane 5 olanzapine 119 opioid analgesic 95 organic cation transporter 62 ototoxicity 100 oxcarbazepine 104 oxidation 76 oxidative stress 116 oxygen rebound 76

P450 enzyme inhibition 138 P450 inhibitor 61 pafenolol 43 PAPS 91

paracellular absorption 38 paracellular pathway 47, 71 paracellular route 64 parallel synthesis 133 paroxetine 92 partition coefficient 2, 9, 10

absence of dissociation or ionization 3 artificial membranes 9 basic drugs 11 calculation 9

chromatographic techniques 9 intrinsic lipophilicity 3 ionic interactions 11 liposomes 9 membrane systems 10 phospholipids 10 shake-flask 9 unilamellar vesicles 10 unionized form 3 passive diffusion 68, 136

peak-to-trough variations 56 peptidic renin inhibitors 8 permeability 136 peroxisome proliferator-activated receptor y 120 PET scanning 28 P-glycoprotein 41, 42, 43, 137 pharmacokinetic modelling 139 pharmacokinetic phase 26 phase II conjugation 90 phenacetin 104 phenol 90, 91, 94 phenolate anion 91 phenytoin 37, 80, 103, 118, 128 pholcodine 55 phospholipid 52, 54 phospholipidosis 102 physiological models 139 physiological time 127 pindolol 51 pirenzepine 30 pKa 136

plasma protein binding 32, 69, 125, 129

polar surface area 45, 136

polyethylene glycol 36

polypharmacology 100

poor absorption 23

poor metabolizers 79

practolol 106

predictive methods 115

pre-systemic metabolism 22

procainamide 109

pro-drug design 43

pro-drug 89

pro-moiety 43

propafenone 79

protein binding 137

proxicromil 102

proximal tubule 67

pulsed ultrafiltration-mass spectrometry 138

QSAR 115, 138

quantitative structure-pharmacokinetic relationships 138

quantitiative structure-metabolism relationships 138

quinone imine 104, 111 r radical stability 84 Raevsky 40 rash 106

reabsorption 68

reactive metabolite 103, 104, 105,

110, 113

real-time SAR 135 receptor occupancy 26, 28, 51 receptor occupation 25 receptor-ligand complex 25 relative metabolic stability 129 remifentanil 89 remoxipride 28 renal clearance 62, 63, 126, 127 renal injury 113 rifabutin 52 rifampicin 52 rifamycin SV 52 rosiglitazone 119 rule-of-five 40

s salbutamol 30 salmeterol 30 SAM 92

SCH 48461 83, 85 screening sequences 134 secondary amines 84 sensitization period 119 serine esterases 87 side-effects 56, 88, 89 sinusoidal carrier systems 60 skin rash 103 slow offset 29, 30

pharmacodynamic action 30 SM-10888 63, 75 small intestine 38 soft-drug 89 solubility 45, 136

species-specific differences 127, 129 steady state concentration 21 clearance 21 half-life 21

intravenous infusion 21 steady state 24, 26, 33, 88 steroid receptors 29 (S)-warfarin 80 Stevens-Johnson syndrome 112 structure-activity relationships 26 structure-toxicity relationships 115 substrate radical 76 sulphamethoxazole 111 sulphate transferases 91 sulphate 93, 95 sulphonamide 107 sulphotransferases 91, 95 phenol-sulphotransferase 91

sulpiride 28, 49 suprofen 112

t tacrine 105 talinolol 42 telenzepine 30 tenidap 113 teratogenicity 100, 103 terfenadine 82 tertiary amine 82 thalidomide 100 thioether adducts 109 thiolate anion 93 thiophene ring 112 thiophene S-oxide 112 thiophene 113 thioridazine 28 thiourea 114

thromboxane A2 receptor antagonists 61 thromboxane receptor antagonists 130 thromboxane synthase inhibitors 61 ticlopidine 112 tienilic acid 112, 127 tissue half-life 54

Tmax 56

tocainide 109 tolbutamide 80, 107, 127 topical administration 88 toxicity 99, 101, 102 idiosyncratic 102 metabolism 102 pharmacology 99 physiochemical properties 101 structure 101 toxicogenomics 116 toxicology 118 toxicophore 108, 115 transcellular diffusion 38 transport proteins 41, 67, 69 transport systems 60 transporter proteins 129, 130, 137 transporter 60, 61, 137 canalicular 60 sinusoid 60 triamterene 37 triazole 72 troglitazone 119 tubular carrier systems 62 tubular pH 69

tubular reabsorption 70, 72, 126 tubular secretion 69, 70 turbidimetry 136

UDP-a-glucuronic acid 90 unbound drug concentration 50 unbound drug 24, 125 GABA uptake inhibitors 6 histamine Hrreceptor antagonists 6 uptake of drugs in the brain 6 urea 42 urine 62, 67

v variability 124 verapamil 68 vesnarinone 111

volume of distribution 17, 32, 51, 64, 124, 136

apparent free volume 32 extracellular water volume 17 plasma volume 17 tissue affinity 17 total body water volume 17

w water solubility 37 white blood cell toxicity 113

z zamifenacin 92, 126 96-well 137

Pharmacokinetics and Metabolism in Drug Design 1 Edited by D. A. Smith, H. van de Waterbeemd, D. K. Walker, R. Mannhold, H. Kubinyi, H. Timmerman I

Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-30197-6 (Hardcover); 3-527-60021-3 (Electronic)



CPC Centrifugal partition chromatography

CoMFA Comparative field analysis

3D-QSAR Three-dimensional quantitative structure-activity relationships

IUPAC International Union of Pure and Applied Chemistry

MLP Molecular lipophilicity potential

RP-HPLC Reversed-phase high performance liquid chromatography

PGDP Propylene glycol dipelargonate

SF Shake flask, referring to traditional method to measure log P or log D Symbols

Alog D Difference between log D in octanol/water and log D in alkane/water

Alog P Difference between log P in octanol/water and log P in alkane/water f Rekker or Leo/Hansch fragmental constant for log P contribution

K Ionization constant

A Polarity term, mainly related to hydrogen bonding capability of a solute log P Logarithm of the partition coefficient (P) of neutral species log D Logarithm of the distribution coefficient (D) at a selected pH, usually assumed to be measured in octanol/water log Doct Logarithm of the distribution coefficient (D) at a selected pH, measured in octanol/water log Dchex Logarithm of the distribution coefficient (D) at a selected pH, measured in cyclohexane/water log D7a Logarithm of the distribution coefficient (D) at pH 7.4

MW Molecular weight n Hansch constant; contribution of a substituent to log P

pK Negative logarithm of the ionization constant Ka

Physicochemistry and Pharmacokinetics

The body can be viewed as primarily composed of a series of membrane barriers dividing aqueous filled compartments. These membrane barriers are comprised principally of the phospholipid bilayers which surround cells and also form intracellular barriers around the organelles present in cells (mitochondria, nucleus, etc.). These are formed with the polar ionized head groups of the phospholipid facing towards the aqueous phases and the lipid chains providing a highly hydrophobic inner core. To cross the hydrophobic inner core a molecule must also be hydrophobic and able to shed its hydration sphere. Many of the processes of drug disposition depend on the ability or inability to cross membranes and hence there is a high correlation with measures of lipophilicity. Moreover, many of the proteins involved in drug disposition have hydrophobic binding sites further adding to the importance of the measures of lipophilicity [1].

At this point it is appropriate to define the terms hydrophobicity and lipophilicity. According to recently published IUPAC recommendations both terms are best described as follows [2]:

Hydrophobicity is the association of non-polar groups or molecules in an aqueous environment which arises from the tendency of water to exclude non-polar molecules

Lipophilicity represents the affinity of a molecule or a moiety for a lipophilic environment. It is commonly measured by its distribution behaviour in a biphasic system, either liquid-liquid (e.g. partition coefficient in 1-octanol/water) or solid-liquid (retention on reversed-phase high-performance liquid chromatography (RP-HPLC) or thin-layer chromatography (TLC) system).

The role of dissolution in the absorption process is further discussed in Section 3.2.

Partition and Distribution Coefficient as Measures of Lipophilicity

The inner hydrophobic core of a membrane can be modelled by the use of an organic solvent. Similarly a water or aqueous buffer can be used to mimic the aqueous filled compartment. If the organic solvent is not miscible with water then a two-phase system can be used to study the relative preference of a compound for the aqueous (hydrophilic) or organic (hydrophobic, lipophilic) phase.

For an organic compound, lipophilicity can be described in terms of its partition coefficient P (or log P as it is generally expressed). This is defined as the ratio of concentrations of the compound at equilibrium between the organic and aqueous phases: p = [drug]organic


1.2 Partition and Distribution Coefficient as Measures of Lipophilicity 3

The partition coefficient (log P) describes the intrinsic lipophilicity of the collection of functional groups and carbon skeleton, which combine to make up the structure of the compound, in the absence of dissociation or ionization. Methods to measure partition and distribution coefficients have been described [3, 4].

Every component of an organic compound has a defined lipophilicity and calculation of partition coefficient can be performed from a designated structure. Likewise, the effect on log P of the introduction of a substituent group into a compound can be predicted by a number of methods as pioneered by Hansch [5-8] (n values), Rekker [9-10] fvalues) and Leo/Hansch [5-7, 11-12] f values).

Partitioning of a compound between aqueous and lipid (organic) phases is an equilibrium process. When in addition the compound is partly ionized in the aqueous phase a further (ionization) equilibrium is set up, since it is assumed that under normal conditions only the unionized form of the drug penetrates the organic phase [13]. This traditional view is shown schematically in Figure 1.1 below. However, the nature of the substituents surrounding the charged atom as well as the degree of de-localization of the charge may contribute to the stabilization of the ionic species and thus not fully exclude partitioning into an organic phase or membrane [14]. An example of this is the design of acidic 4-hydroxyquinolones (Figure 1.2) as glycine/ NMDA antagonists [15]. Despite a formal negative charge these compounds appear to behave considerable ability to cross the blood-brain barrier.

In a study of the permeability of alfentanil and cimetidine through Caco-2 cells, a model for oral absorption, it was deduced that at pH 5 about 60 % of the cimetidine transport and 17% of the alfentanil transport across Caco-2 monolayers can be attributed to the ionized form [16] (Figure 1.3). Thus the dogma that only neutral species can cross a membrane has been challenged recently.

The intrinsic lipophilicity (P) of a compound refers only to the equilibrium of the unionized drug between the aqueous phase and the organic phase. It follows that the

(ionised drug) < * (union drug)






Fig. 1.1 Schematic depicting the relationship between log P 1. Is a function of acid/base strength pK^ and log D and pKa. 2. Is a function of P (log P)

Fig. 1.1 Schematic depicting the relationship between log P 1. Is a function of acid/base strength pK^ and log D and pKa. 2. Is a function of P (log P)

Fig. 1.3 Transportation rate of basic drugs across Caco-2 monolayers: alfentanil, rapid transport; cimetidine, slow transport [16].

remaining part of the overall equilibrium, i.e. the concentration of ionized drug in the aqueous phase, is also of great importance in the overall observed partition ratio. This in turn depends on the pH of the aqueous phase and the acidity or basicity (pKa) of the charged function. The overall ratio of drug, ionized and unionized, between the phases has been described as the distribution coefficient (D), to distinguish it from the intrinsic lipophilicity (P). The term has become widely used in recent years to describe, in a single term the effective (or net) lipophilicity of a compound at a given pH taking into account both its intrinsic lipophilicity and its degree of ionization. The distribution coefficient (D) for a monoprotic acid (HA) is defined as:

where [HA] and [A-] represent the concentrations of the acid in its unionized and dissociated (ionized) states respectively. The ionization of the compound in water is defined by its dissociation constant (Ka) as:

sometimes referred to as the Henderson-Hasselbach relationship. Combination of Eqs. (1.1)-(1.3) gives the pH-distribution (or 'pH-partition') relationship:

more commonly expressed for monoprotic organic acids in the form of Eqs. (1.5) and (1.6), below:

For monoprotic organic bases (BH+ dissociating to B) the corresponding relationships are:

or or

1.3 Limitations in the Use of 1-Octanol | 5

From these equations it is possible to predict the effective lipophilicity (log D) of an acidic or basic compound at any pH value. The data required in order to use the relationship in this way are the intrinsic lipophilicity (log P), the dissociation constant (pKa), and the pH of the aqueous phase. The overall effect of these relationships is the effective lipophilicity of a compound, at physiological pH, is the log P value minus one unit of lipophilicity, for every unit of pH the pKa value is below (for acids) and above (for bases) pH 7.4. Obviously for compounds with multifunctional ioniz-able groups the relationship between log P and log D, as well as log D as function of pH become more complex [17]. For diprotic molecules there are already 12 different possible shapes of log D-pH plots.

Limitations in the Use of 1-Octanol

Octanol is the most widely used model of a biological membrane [18] and logD;.4 values above 0 normally correlate with effective transfer across the lipid core of the membrane, whilst values below 0 suggest an inability to traverse the hydrophobic barrier.

Octanol, however, supports H-bonding. Besides the free hydroxyl group, octanol also contains 4 % v/v water at equilibrium. This obviously conflicts with the exclusion of water and H-bonding functionality at the inner hydrocarbon core of the membrane. For compounds that contain functionality capable of forming H-bonds, therefore, the octanol value can over-represent the actual membrane crossing ability. These compounds can be thought of as having a high hydration potential and difficulty in shedding their water sphere.

Use of a hydrocarbon solvent such as cyclohexane can discriminate these compounds either as the only measured value or as a value to be subtracted from the octanol value (Alog P) [19-21]. Unfortunately, cyclohexane is a poor solvent for many compounds and does not have the utility of octanol. Groups which hydrogen bond and attenuate actual membrane crossing compared to their predicted ability based on octanol are listed in Figure 1.4. The presence of two or more amide, carboxyl functions in a molecule will significantly impact on membrane crossing ability and will need substantial intrinsic lipophilicity in other functions to provide sufficient hydrophobicity to penetrate the lipid core of the membrane.

Further Understanding of log P

Unravelling the Principal Contributions to log P

The concept that log P or log D is composed of two components [22], that of size and polarity is a useful one. This can be written as Eq. (1.9), log P or log D = a • V - A

where V is the molar volume of the compound, A a general polarity descriptor and a is a regression coefficient. Thus the size component will largely reflect the carbon skeleton of the molecule (lipophilicity) whilst the polarity will reflect the hydrogen bonding capacity. The positioning of these properties to the right and left of Figure 1.4 reflects their influence on the overall physicochemical characteristics of a molecule.

Octanol/Cyclohexane Ratio (H-bonding)

Sec Amide





Pn Amine












Fig. 1.4 Functionality and H-bonding.

Fig. 1.4 Functionality and H-bonding.

Hydrogen Bonding

Hydrogen bonding is now seen as an important property related to membrane permeation. Various scales have been developed [23]. Some of these scales describe total hydrogen bonding capability of a compound, while others discriminate between donors and acceptors [24]. It has been demonstrated that most of these scales show considerable intercorrelation [25].

Lipophilicity and H-bonding are important parameters for uptake of drugs in the brain [26]. Their role has e.g. been studied in a series of structurally diverse sedating and non-sedating histamine Hrreceptor antagonists [27]. From these studies a decision tree guideline for the development of non-sedative antihistamines was designed (see Figure 1.5).

GABA (y-aminobutyric acid) is a major neurotransmitter in mammals and is involved in various CNS disorders. In the design of a series of GABA uptake inhibitors a large difference in in vivo activity between two compounds with identical IC50 val-

1.4 Further Understanding of log P 7

Fig. 1.5 Decision tree for the design of non-sedative Hrantihistaminics. Log D is measured at pH 7.4, while Alog P refers to compounds in their neutral state (redrawn from reference [27]).

good brain penetration ues was observed, one compound being devoid of activity [28]. The compounds have also nearly identical pKa and log Doct values (see Figure 1.6) and differ only in their distribution coefficient in cyclohexane/water (log Dchex). This results in a Alog D of 2.71 for the in vivo inactive compounds, which is believed to be too large for CNS uptake. The active compound has a Alog D of 1.42, well below the critical limit of approximately 2. Besides this physicochemical explanation further evaluation of metabolic differences should complete this picture. It should be noted that the concept of using the differences between solvent systems was originally developed for compounds in their neutral state (Alog P values, see Section 2.2). In this case two zwitterions are being compared, which are considered at pH 7.4 to have a net zero charge, and thus the Alog P concept seems applicable.

1.4 Further Understanding of log P 7

Properties of GABA-uptake inhibitors [28].

Properties of GABA-uptake inhibitors [28].




0.11 mM

0.1 mM

in vivo









log £>«„„



Alog D



8 | 1 Physicochemistry 1.4.3

Molecular Size and Shape

Molar volume as used in Eq. (1.9) is one way to express the size of a compound. It is very much related to molecular surface area. For convenience often the molecular weight (MW) is taken as a first estimate of size. It is also useful to realize that size is not identical to shape.

Many companies have tried to develop peptidic renin inhibitors. Unfortunately these are rather large molecules and not unexpectedly poor absorption was often observed. The role of physicochemical properties has been discussed for this class of compounds. One of the conclusions was that compounds with higher lipophilicity were better absorbed from the intestine [29]. Absorption and bile elimination rate are both MW-dependent. Lower MW results in better absorption and less bile excretion. The combined influence of molecular size and lipophilicity on absorption of a series of renin inhibitors can be seen from Figure 1.7. The observed iso-size curves are believed to be part of a general sigmoidal relationship between permeability and lipophilicity [30-31] (for further details see Chapter 3).

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