Lipophilicity biomembrane

As evident from the previous discussion, a major barrier to the use of peptides as clinically useful drugs has to do with their poor delivery properties, because proteolytic enzymes present at most routes of administration are able to quickly metabolize most peptides. Peptides and proteins are, for the most part, hydrophilic in nature and, for this reason, do not readily penetrate lipophilic biomembranes. As well, they have short biological half-lives because of rapid metabolism and clearance, all of which deters from their efficient use in drug therapy. It is for these reasons that alternative drug delivery methods for peptides and proteins are an area of particular interest to the pharmaceutical industry. 

Lipophilicity is intuitively felt to be a key parameter in predicting and interpreting permeability and thus the number of types of lipophilicity systems under study has grown enormously over the years to increase the chances of finding good mimics of biomembrane models. However, the relationship between lipophilicity descriptors and the membrane permeation process is not clear. Membrane permeation is due to two main components the partition rate constant between the lipid leaflet and the aqueous environment and the flip-flop rate constant between the two lipid leaflets in the bilayer [13]. Since the flip-flop is supposed to be rate limiting in the permeation process, permeation is determined by the partition coefficient between the lipid and the aqueous phase (which can easily be determined by log D) and the flip-flop rate constant, which may or may not depend on lipophilicity and if it does so depend, on which lipophilicity scale should it be based ... 

Pignatello R, Toth I, Puglisi G (2001) Structural effects of lipophilic methotrexate conjugates on model phospholipid biomembranes. Thermochim. Acta 380 255-264. 

The difficulty with HLB as an index of physicochemical properties is that it is not a unique value, as the data of Zaslavsky et al. (1) on the haemolytic activity of three alkyl mercaptan polyoxyethylene derivatives clearly show in Table 1. Nevertheless data on promotion of the absorption of drugs by series of nonionic surfactants, when plotted as a function of HLB do show patterns of behaviour which can assist in pin-pointing the necessary lipophilicity required for optimal biological activity. It is evident however, that structural specificity plays a part in interactions of nonionic surfactants with biomembranes as shown in Table 1. It is reasonable to assume that membranes with different lipophilicities will"require" surfactants of different HLB to achieve penetration and fluidization one of the difficulties in discerning this optimal value of HLB resides in the problems of analysis of data in the literature. For example, Hirai et al. (8 ) examined the effect of a large series of alkyl polyoxyethylene ethers (C4,C0, Cj2 and C 2 series) on the absorption of insulin through the nasal mucosa of rats. Some results are shown in Table II. 

Membrane permeability is another important parameter for drugs, because it is related to intestinal absorption and brain penetration. Lipophilicity is also useful in predicting these phenomena. In addition, liposome with phospholipid would be more reliable for measuring biomembrane permeability. Recently, some groups reported an EKC approach with phospholipid vesicles (56-58). 

F Beigi, P Lundahl. Immobilized biomembrane chromatography of highly lipophilic drugs. J Chromatogr A 852 313-317, 1999. 

The function of a transport parameter is to model the transfer of the bas from the aqueous phase to biomembrane and bas receptor. The transport parameter is frequently also referred to as a hydrophobicity or lipophilicity parameter, the former term is no doubt preferred by pessimists and the latter by optimists. Unfortunately, there has been no attempt at the standardization of nomenclature in this field (A rose by any other name. ..). As is usually the case under these circumstances far too much heat and very little light results. 

A final example of the use of dithiolenes comes from the work of Grimaldi and Lehn,222 and Ohki, Tagaki and Ueno.223 These groups used tetraphenylnickeldithiolene as a redox potential driven electron carrier and cation carrier through artificial membranes. Lipophilic cocarriers were employed to generate a multicomponent carrier system, in which charge equalization occurs. Applications to biomembranes, ion separation and related processes were suggested. 

The volume of distribution of a peptide or protein drug is determined largely by its physico-chemical properties (e. g., charge, lipophilicity), protein binding, and dependency on active transport processes. Due to their large size - and therefore limited mobility through biomembranes - most therapeutic proteins have small volumes of distribution, typically limited to the volumes of the extracellular space [26, 51]. 

Lipophilic compounds, such as the various terpenoids, tend to associate with other hydrophobic molecules in a cell these can be biomembranes or the hydrophobic core of many proteins and of the DNA double helix [10,18,24,25]. In proteins, such hydrophobic and van der Waals interactions can also lead to conformational changes, and thus protein inactivation. A major target for terpenoids, especially saponins, is the biomembrane. Saponins (and, among them, the steroid alkaloids) can change the fluidity of biomembranes, thus reducing their function as a permeation barrier. Saponins can even make cells leaky, and this immediately leads to cell death. This can easily be seen in erythrocytes when they are attacked by saponins these cells burst and release hemoglobin (hemolysis) [1,6,17]. Among alkaloids, steroidal alkaloids (from Solanaceae) and other terpenoids have these properties. 

Dermal absorption, the process by which a substance is transported across the skin and taken up into the living tissue of the body (USEPA, 1992), is a complex process. The skin is a multilayered biomembrane with particular absorption characteristics. It is a dynamic, living tissue and as such its absorption parameters are susceptible to constant changes. Upon contact with the skin, a portion of the substance can penetrate into the non-viable stratum comeum and may subsequently reach the viable epidermis, the dermis and, ultimately, the vascular network. During the absorption process, the compound may be subject to biotransformafion (Noonan and Wester, 1989). The stratum comeum provides the skin its greatest barrier function against hydrophilic compounds, whereas the viable epidermis is most resistant to highly lipophilic compounds (Flynn, 1985). 

During fhe pasf 10 years, if became obvious fhaf planfs also contain a high diversity of ABC fransporfers (Martinoia et al., 2002 Rea, 2007). These membrane profeins, which can pump lipophilic compounds across biomembranes, are driven by ATP. They are common in animal cells and important for mulfidrug resisfance observed in pafienfs undergoing chemofherapy (Dean et al., 2001 Linfon, 2006). Two fypes of efflux pumps, which belong fo the ABC... 

Lipophilic compounds will interfere not only with the biomembranes of microbes and herbivores, but also with those of the producing plant. In order to avoid autotoxicity, plants cannot store these compounds in the vacuole but usually sequester them on the cuticle, in dead resin ducts or cells, which are lined not by a biomembrane but by an impermeable solid barrier (Fig. 1.5). In some cases, the compounds are combined with a polar molecule, so that they can be stored as more hydrophilic chemicals in the vacuole. 

The enzyme systems involved in biotransformation are largely substrate-nonspecific. Therefore, they are not only able to convert exogenous or endogenous lipophilic substances into water-soluble metabolites, but also to intervene in the metabolism of endogenous substances (e. g. bile adds, hormones). These enzymes are mainly localized structure-bound in the biomembranes or found non-structure-bound as soluble enzymes. About 5% of the total protein reserves of the liver are needed for the bio transformation of enzymes. 

Some ionised drug molecules can traverse the lipophilic gut membrane by combining with an ion of opposite charge (a counter ion) to form an ion pair. The ion pair, although composed of two ionic species, behaves as a neutral molecule with a high partition coefficient and can cross biomembranes effectively Quaternary ammonium compounds, which are charged at all values of pH, may be absorbed into the body in this way ... 

Many polar active molecules, selected through in vitro screening tests are unable to cross the biomembranes and their bioavailability is particularly low. Attaching a very lipophilic moiety can sometimes help to overcome this drawback. 

The biomembrane passage of a drug depends primarily on its physicochemical properties and especially on its partition coefficient (Chapters 22 and 34). Thus, the transient attachment of a lipophilic carrier group to an active principle can provide a better bioavailability, mostly by facifitating cell membrane crossing by passive diffusion. Peroral absorption, as well as rectal absorption, ocular drug delivery and dermal drug delivery, are dependent on passive diffusion. Finally, lipophilic carriers can sometimes be useful to reduce first-pass metabolism. ... 

The integrity of biomembranes is of ultimate importance for the functioning of cells and of all neuronal activities. Compounds which disturb biomembranes and thus make cells leaky, are usually strong cell poisons and interfere with membrane potential. Natural products which exhibit these properties are either very lipophilic or amphiphilic, such as mono-, sesqui- and diterpenes or triterpene and steroid saponins, respectively. 

Steroidal alkaloids, such as solanine and tomatine which are present in many members of the Solanaceae, can form complexes with the cholesterol and other lipids present in biomembranes. Important for this interaction is the presence of a lipophilic portion of the molecule (given by the steroidal moiety) and a hydrophilic portion (provided by the sugar side chain). Whereas the lipophilic moiety "dives" into the lipophilic interior of the membrane and interacts with the structurally similar cholesterol, the hydrophilic side chain remains outside and binds to external sugar receptors. Since phospholipids are in a continuous motion (spinning around their axis and horizontal movements), a tension easily builds up which leads to membrane disruption i.e. transient "holes" form in the biomembrane rendering the cell leaky. Since particular steroidal alkaloids can specifically interact with receptors, ion channels or transmitter... 

Ion Is absorbed by passive transport. Passive transport Is diffusion-controlled and only permits the transit of lipophilic molecules. Substantial evidence shows lipophilic Fe(IIl) complexes traverse biomembranes In the same manner as lipophilic complexes of other metals. Nickel could affect the metabolism of the lipophilic Fe(III) complexes In at least two ways. 

Solid-state F solid-state NMR spectroscopy are used to analyze the structure and dynamics of lipophilic drugs and peptides embedded in biomembranes. Here experiments using the homonuclear dipolar couplings of trifluoromethyl labels can provide valuable parameters such as orientational constraints and/or distances. 

Total solubility (C ) of the active pharmaceutical ingredient in an aqueous medium and the coefficient of penetration (P) of an active pharmaceutical ingredient through the lipophilic part of biomembranes have been represented as binary scale (0—low property value, 1— high property value). 

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