Lipophilicity and protein binding

Given the data in Table 10.9 it is not surprising to find that the extent of protein binding of many dmgs is a linear function of their partition coefficient P (or log P). A linear equation 

Binding to protein outside of the plasma may determine the characteristics of drug action or transport. Muscle protein may bind 

When binding occurs with high affinity and the total amount of dmg in the body is low, drug will be present almost exclusively in the plasma. Dmgs with lower association constants (K 10 or 10 0 will be distributed more in the body water spaces. When the number of available binding sites is reduced by a second drug, it will appear as if there has been an increase in overall dmg concentration. 

Although dmgs are predominantly bound to albumin, the amount taken up by erythrocytes must not be neglected, as can be seen in Fig. 10.22. 

More directly, the effect of protein binding on antibiotic action is worth considering. 

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Chou, C. H., Rowland, M. Relationship between lipophilicity and protein binding of a homologous series of barbimrates. Chin. Pharm. f 2002, 54, 87-94. 

In the study by Parrott et al. [7], a generic PBPK model was applied to predict plasma profiles after intravenous and oral dosing to the rat for a set of 68 compounds from six different chemical classes. The compounds were selected without particular bias and so are considered representative of current Roche discovery compounds. The physicochemical properties of the compounds are rather different from those of marketed compounds in particular they have higher lipophilicity (mean logP = 4) and lower aqueous solubility as well as a tendency to be neutral at physiological pH. The more extreme property values can present experimental determination challenges and so for consistency all predictions were made on the basis of calculated lipophilicity and protein binding while in vitro... 

The use of antibiotics in aerosol form has been reviewed by several authors, among them Stout and Derendorf (115). Several factors affect the penetration of antibiotics into sputum following systemic administration, among these are chemical properties, such as the molecular weight, lipophilicity, and protein bind-... 

Lipooligosaccharide (LOS) bacterial, 25 498 Lipophilic amphiphiles, 24 154-155 Lipophilic interaction dominated substrate recognition, 16 783-786 Lipophilic moieties, 8 706t Lipopolysaccharides (LPS), 4 706 11 47 BPI protein ability to neutralize, 18 257 peptide and protein binding affinity to, 18 256... 

Chemicals must be distributed to their site of action to manifest a biological effect. The distribution process is controlled by passive diffusion, active transport and protein binding in blood and tissues. In general smaller, hydrophilic molecules are distributed more quickly and to a greater extent to well-perfused compartments than are larger lipophilic molecules. Lipophilic molecules tend to become concentrated in slowly perfused compartments like bone and in fat stores. 

DISTRIBUTION AND SERUM LEVEL MONITORING Once absorbed, tricychc antide pressants are widely distributed. They are relatively lipophilic and strongly bind to plasma proteins and constituents of tissues, leading to apparent volumes of distribution as high as 10-50 L g. The tendency of tricyclic antidepressants and their ring-hydroxy metabolites to accumulate in cardiac tissue adds to their cardiotoxicity. Serum concentrations of antidepressants that correlate meaningfully with clinical effects are only established for a few tricychc antidepressants (particularly amitriptyline. 

The lipophilicity of a compound is often considered as an important design factor since it is related to processes such as absorption, brain uptake, volume of distribution and protein binding. This property is often expressed as the partition coefficient (log P) or distribution coefficient (log D, typically measured at pH 7.4). By several lines of evidence it was shown that log P values should be... 

Dmg distribution into tissue reservoirs depends on the physicochemical properties of the dmg. Tissue reservoirs include fat, bone, and the principal body organs. Access of dmgs to these reservoirs depends on partition coefficient, charge or degree of ionization at physiological pH, and extent of protein binding. Thus, lipophilic molecules accumulate in fat reservoirs and this accumulation can alter considerably both the duration and the concentration—response curves of dmg action. Some dmgs may accumulate selectively in defined tissues, for example, the tetracycline antibiotics in bone (see Antibiotics,tetracyclines). 

The distribution of a drug in the body is largely driven by its physicochemical properties and in part for some compounds by the contribution of transporter proteins [17]. By using the Oie-Tozer equation and estimates for ionization (pfCj). plasma protein binding (PPB) and lipophilicity (log quite robust predictions for the volume of distribution at steady state (Vdss), often within 2-fold of the observed value, can be made [18]. 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

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