Lipophilicity of the drug

An analysis of partition coefficient data and drug solubilities in PCL and silicone rubber has been used to show how the relative permeabilities in PCL vary with the lipophilicity of the drug (58,59). The permeabilities of copolymers of e-caprolactone and dl-lactic acid have also been measured and found to be relatively invariant for compositions up to 50% lactic acid (67). The permeability then decreases rapidly to that of the homopolymer of dl-lactic acid, which is 10 times smaller than the value of PCL. These results have been discussed in terms of the polymer morphologies. 

Since lipophilic molecules have affinity for both the membrane lipid and the serum proteins, membrane retention is expected to decrease, by the extent of the relative lipophilicities of the drug molecules in membrane lipid versus serum proteins, and by the relative amounts of the two competitive-binding phases [see Eqs. (7.41)-(7.43)]. Generally, the serum proteins cannot extract all of the sample molecules from the phospholipid membrane phase at equilibrium. Thus, to measure permeability under sink conditions, it is still necessary to characterize the extent of membrane retention. Generally, this has been sidestepped in the reported literature. 

Passive diffusion through the lipid bilayer of the epithelium can be described using the partition coefficient between octanol/water (log P) and A log P (the difference between the partition into octanol/water and heptane/ethylene glycol or heptane/ octanol) [157, 158], The lipophilicity of the drug (log P) (or rather log D at a certain pH) can easily be either measured or calculated, and is therefore generally used as a predictor of drug permeability. Recently, a method using artificial membrane permeation (PAMPA) has also been found to describe the passive diffusion in a similar manner to the Caco-2 cell monolayers [159]. 

The lipophilicity of the drug can affect cell membrane permeability. The hydrophobicity allows the drug to favorably interact with membrane receptors. However, the cationic nature can affect the movement of cations such as Na+ and Ca+ across the cell membrane. 

The lipophilicity of the drug, as reflected by its w-octanol/buffer partition coefficient (PC), with the optimum PC being in the range 10-100. 

The lipophilicity of the drug candidate is informative because drag candidates with a log D7 4 greater than 1 are likely to require biotransformation to more polar metabolites to facilitate their elimination in urine or bile. The chemical structure of the drug candidate provides important information on the potential for enzymes other than CYP to be involved in its metabolism. Table 9 shows a variety... 

The pH dependence of Ca2+ displacement for selected compounds is shown in Figure 3.1. It can be concluded that the protonation of drugs is a precondition for binding to the polar head groups of phospholipids. The degree of binding is modified by the lipophilicity of the drug molecule. 

Sakane,T., Akizuki, M., Yamashita, S., Nadai,T., Hashida, M., and Sezaki, H. (1991),The transport of a drug to the cerebrospinal fluid directly from the nasal cavity The relation to the lipophilicity of the drug, Chem. Pharm. Bull., 39,2456-2458. 

However, more important physicochemical properties in terms of ocular bio-availability are the ones that affect the corneal permeability of the active compound. These include the lipophilicity of the drug as reflected by its n-octanol-water partition coefficient [32], the molecular size and shape [33], the charge [34], and the acid-base properties as determined by its pK [35]. 

The synthetic and metabolic capacity of this patient s liver is unlikely to be affected by cholestasis. However, consideration needs to be given to protein binding (patient has hyperbilirubinaemia) excretion of the drug or metabolites in bile (patient has cholestasis) and lipophilicity of the drug (some lipophilic drugs require bile salts for absorption and these would be reduced in cholestasis). 

Lipophilicity of the drug (some lipophilic drugs require bile salts for absorption and these would be reduced in cholestasis). 

Different alkyl groups on a nitrogen atom may alter the basicity and/or lipophilicity of the drug and thus affect how strongly the drug binds to its binding site or how easily the compound crosses membrane barriers (see Chapter 8). 

The partition coefficient refers to the intrinsic lipophilicity of the drug, in the context of the equilibrium of unionized drug between the aqueous and organic phases. If the drug has more than one ionization center, the distribution of species present will depend on the pH. The concentration of the ionized drug in the aqueous phase will therefore have an effect on the overall observed partition coefficient. This leads to the definition of the distribution coefficient (log D) of a compound, which takes into account the dissociation of weak acids and bases. 

The chemical form of the drug can be very important for ocular bioavailability. Changing the salt can affect the solubility and lipophilicity of the drug. For example, dexa-methasone acetate ester has the preferred solubility and partition coefficient properties for corneal permeation compared to the very water-soluble phosphate salt or very lipophilic freebase. 

Conversely, if the drug is hydrophilic, the drug will penetrate to a lesser extent into tissue consequently, the plasma concentration will be higher and / smaller. It therefore is accurate to state that the value of V is influenced by the lipophilicity of the drug molecules. 

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