PARTITIONING INTO LIPOSOMES in Visual Studio .NET

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PARTITIONING INTO LIPOSOMES
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details were coarse, it was apparent that different drugs position in different locations of the bilayer For example, amlodipine is charged when it partitions into a bilayer at physiological pH; the aromatic dihydropyridine ring is buried in the vicinity of the carbonyl groups of the acyl chains, while the NH3 end points toward the aqueous phase, with the positive charge located near the phosphate negativecharge oxygen atoms [426 428] A much more lipophilic molecule, amiodarone (weak base with pKa 91 [pION]), positioned itself closer to the center of the hydrocarbon interior [425]
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54 THERMODYNAMICS OF PARTITIONING: ENTROPY- OR ENTHALPY-DRIVEN Davis et al [394] studied the thermodynamics of the partitioning process of substituted phenols and anisoles in octanol, cyclohexane, and dimyristoylphosphatidylcholine (DMPC) at 22 C (which is below the gel liquid transition temperature of DMPC) Table 51 shows the results for 4-methylphenol The phenol partitioned into the lipid phases in the order DMPC > octanol > cyclohexane, as indicated by Gtr Thus, the free energy of transfer into DMPC was greater than into octanol or cyclohexane Partitioning was generally-entropy driven, but the components of the free energy of transfer were greatly different in the three lipid systems (Table 51) Octanol was the only lipid to have an exothermic heat of transfer (negative enthalpy), due to H-bond stabilization of the transferred solute, not found in cyclohexane Although H tr in the DMPC system is a high positive number (endothermic), not favoring partitioning into the lipid phase, the entropy increase ( 1141 eu) was even greater, more than enough to offset the enthalpy destabilization, to end up an entropy-driven process The large H tr and Str terms in the DMPC system are due to the disruption of the ordered gel structure, found below the transition temperature The partition of lipophilic drugs into lipid phases is often believed to be entropy driven, a hydrophobic effect Bauerle and Seelig [395] studied the thermodynamics of amlodipine and nimodipine binding to phospholipid bilayers (above the transition temperature) using highly sensitive microcalorimetry The partitioning of the drugs into the lipid bilayer was enthalpy-driven, with H tr 385 kJ mol 1 bound amlodipine The entropy of transfer is negative, contrary to the usual interpretation
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TABLE 51 Energy of Transfer (kJ/mol) into Lipid Phase for 4-Methylphenol Component H tr T Str Gtr DMPC 920 1141 221 Octanol 73 92 165 Cyclohexane 186 222 36
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ELECTROSTATIC AND HYDROGEN BONDING IN A LOW-DIELECTRIC MEDIUM
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of the hydrophobic effect Thomas and Seelig [397] found the partitioning of the Ca2 antagonist, unarizine (a weak base), also to be predominantly enthalpydriven, with Htr 221 kJ mol 1, again at odds with the established ideas of entropydriven partitioning of drugs The same surprise was found for the partitioning of paclitaxil [398] These observations thus appear to suggest that drugs partition into membrane phases because they are lipophilic, and not because they are hydrophobic! This needs to be investigated more extensively, using microcalorimetry
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55 ELECTROSTATIC AND HYDROGEN BONDING IN A LOW-DIELECTRIC MEDIUM Section 334 pointed out that cosolvents alter aqueous ionization constants; as the dielectric constant of the mixture decreases, acids appear to have higher pKa values and bases appear (to a lesser extent than acids) to have lower values A lower dielectric constant implies that the force between charged species increases, according to Coulomb s law The equilibrium reaction in Eq (31) is shifted to the left in a decreased dielectric medium, which is the same as saying that pKa increases Numerous studies indicate that the dielectric constant in the region of the polar head groups of phospholipids is $32, the same as the value of methanol [381,446 453] Table 52 summarizes many of the results These and other values [381,406] allow us to depict the dielectric spectrum of a bilayer, shown in Fig 52 Given this view, one can think of the phospholipid bilayer as a dielectric microlamellar structure; as a solute molecule positions itself closer to the center of the hydrocarbon region, it experiences lower dielectric eld (Fig 52) At the very core, the value is near that of vacuum A diatomic molecule of Na Cl in vacuum would require more energy to separate into two distinct ions than that required to break a single carbon carbon bond! This means that ions will not easily enter the interior of bilayers without rst forming contact ion pairs It is reasonable to imagine that simple drug counterion pairs, such as (BH Cl ) will undergo exchange of charge pairs (BH for Na originally in the vicinity of PO ) on entering the head-group region, to form, PO HB), with the release of Na and Cl , as depicted in for example, ( Fig 51 We called such an imagined pairing SIP in Section 51 [149] mem An interesting hypothesis may be put forward The interfacial pKa (Fig 51) that a solute exhibits depends on the dielectric environment of its location in the bilayer Simple isotropic water-miscible solvents may be used to approximate mem pKa Pure methanol (E 32), may do well for the bilayer zone containing the phosphate groups; pure 1,4-dioxane (E 2) may mimic some of the dielectric properties of the hydrocarbon region It appears that ps Ka values of several weak bases, when mem extrapolated to 100% cosolvent, do approximate pKa values [119,162,172] ndez and Fromherz made favorable comparisons using dioxane [448] Ferna This idea is of considerable practical use, and has been largely neglected in the literature
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