Zwitterions can be predominant in membrane penetration of drugs: experimental proof

The complete set of species-specific partition coefficients was determined, and the predominant contribution of zwitterionic species to the overall lipophilicity was experimentally proven for the first time. The compounds studied were the amphoteric eburnane alkaloid cis- and trans-apovincaminic acids of therapeutic interest. Partition of the individual microspecies was mimicked by model compounds of the closest possible similarity, and then correction factors were determined and introduced. The noncharged microspecies of the cis-epimer is 30?900 times as lipophilic as its zwitterionic protonation isomer, while the analogous ratio for the trans-epimer is around 15?800. Due to the overwhelming dominance of the zwitterionic form, however, its contribution to the overall lipophilicity exceeds 8 and 5 times that of the noncharged form for the two epimers, respectively. The lipophilicity profile of these zwitterionic compounds is expressed, calculated, and depicted in terms of species-specific lipophilicities over the entire pH range.     

Determination of lipophilicity of two quinolone antibacterials, ciprofloxacin and grepafloxacin, in the protonation equilibrium.

The objective of this study was to compare protonation equilibrium and lipophilicity of two quinolone antibacterials, grepafloxacin (GPFX) and ciprofloxacin (CPFX), in order to give an insight into effects on the physicochemical properties by slight structural motifs. The protonation equilibrium was investigated by a spectrophotometry. Macro- and micro-dissociation constants were simultaneously determined, based on nonlinear regression analysis using the MULTI program, and then microspecies distribution could be described accordingly. Zwitterionic microspecies predominated at isoelectrical point (pI) for both drugs, and the concentration ratio of neutral to zwitterionic forms was near 4-fold greater for GPFX than that for CPFX. The apparent partition coefficient (D(O/B,pH)) versus pH profiles had the shape of a parabolic curve in an n-octanol/buffer system, and reached the maximum around pI for both, respectively. Moreover, two introduced methyl groups in GPFX increased not only intrinsic lipophilicity but also neutral microspecies fraction relative to CPFX, and D(O/B,pH) of GPFX was consequently far higher than that of CPFX. The results emphasized that there were significant differences in protonation equilibrium and lipophilicity between GPFX and CPFX, which conduced to explaining their different behavior in terms of antibacterial activities and pharmacokinetics.     

Transdermal Delivery of Narcotic Analgesics: Comparative Permeabilities of Narcotic Analgesics Through Human Cadaver Skin

Relationships between the in vitro permeation rates of select narcotic analgesics through human skin and their physicochemical properties were investigated by following the permeation kinetics of six representative compounds in small diffusion cells. The relative permeability coefficients of three phenylpiperidine analogues, meperidine, fentanyl, and sufentanil, all measured on a single piece of skin, were 3.7 × 10^–3, 5.6 × 10^–3, and 1.2 × 10^–2 cm/hr, respectively. Using membranes from the same skin section, the permeability coefficients of three opioid alkaloids, morphine, codeine, and hydromorphone, were considerably lower, at 9.3 × 10^–6, 4.9 × 10^–5, and 1.4 × 10^–5 cm/hr, respectively. The high permeability coefficients of the former compounds are due to their highly lipophilic nature as reflected in high octanol/water partition coefficients and low solubility parameters. Generally, the permeability coefficients of the narcotics increase as the lipophilicity increases. When viewed in literature perspective, the data suggest that aqueous tissue control of transport is approached in the case of the phenylpiperidine analogues, all of which have K _{octanol/water} values greater than 40. Permeability coefficients of fentanyl and sufentanil were also determined as a function of pH over the pH range 7.4 to 9.4, in this instance with membranes prepared from additional samples of skin. The permeability coefficients of each drug varied less than threefold over the pH range, a behavior consistent with the highly hydrophobic natures of the compounds. The low permeability coefficients of morphine, codeine, and hydromorphone coupled with their low potencies make these drugs poor transdermal candidates. It appears that fentanyl and sufentanil can be successfully transdermally delivered.     

Protonation equilibrium and lipophilicity of moxifloxacin

This study was performed to characterise the protonation equilibrium at the molecular level and pH-dependent lipophilicity of moxifloxacin. After determining macro- and micro-constants, distribution features of four microspecies in aqueous phase were assessed. The apparent partition coefficient versus pH profile of moxifloxacin showed a parabolic curve in n-octanol/buffer system which reached near pI. The true partition coefficient was calculated from the log P(app) and microconstants values.     

In-vitro and in-vivo studies of cefpirom using bile salts as absorption enhancers

Cephalosporins have to be administered by injection because of the poor intestinal absorption of the orally delivered drugs. Because of the obvious drawbacks of drug delivery by injection, the development of alternatives with enhanced oral bioavailability is receiving much attention in pharmaceutical research. Cefpirom (Cp) is a new semi-synthetic amino-2-thiazolyl-methoxyimino cephalosporin that has been substituted in position 3 with a cyclopenteno-pyridinium group in order to create a zwitterionic compound. It exhibits highly hydrophilic properties, as shown from its extremely low partition coefficient, and therefore its lipophilicity was increased using bile salts. The effect of this on the partition coefficients determined in the n-octanol/buffer system was confirmed using an in-vitro transport model with artificial and biological membranes. The pharmacokinetic properties of Cp were investigated in rabbits after intraduodenal administration with and without bile salts. Furthermore, the physiological compatibility of the bile salts was investigated using active D-glucose transport.     

Characterization of potential NMDA and cholecystokinin antagonists. II. Lipophilicity studies on 2-methyl-4-oxo-3H-quinazoline-3-alkyl-carboxylic acid derivatives

The lipophilicity of 17 newly synthesized potential NMDA and cholecystokinin antagonist 2-methyl-4-oxo-3H-quinazoline-3-alkyl-carboxylic acid derivatives has been investigated. The apparent partition coefficients of two amphoteric compounds of overlapping protonation (Q1 and Q2) were determined by shake-flask method and converted into true log P values using the protonation microconstants. The difference between their lipophilicity expressed with the true partition coefficients was less, than it could be expected from the 2D structures and was explained with conformational preferences and formation of intramolecular interactions. Out of the other 15 monoprotic quinazolone compounds the lipophilicity of ten molecules (Q8-Q17, experimental set) was determined by TLC method with the help of a calibration set consisting of 12 standard molecules, five quinazolones (Q3-Q7) and seven pyrido[1,2-a]pyrimidines (PP1-PP7). In order to justify the suitability of pyrido-pyrimidines as standards for the chromatographic log P determination of quinazolones, first Q3-Q7 were examined by TLC and HPLC using PP1-PP7 for calibration. Data showed good agreement of results obtained by shake-flask and two different chromatographic methods indicating the similar chromatographic behavior of the two bicyclic systems and the relevance of PP1-PP7 to extend the calibration set of quinazolones. The obtained log P values proved mostly the expected structure-activity relationships. Some findings, however, have revealed specific partition behavior of the compounds providing useful information in the estimation of their pharmacokinetics, and these are discussed in the paper.     

When is a trifluoromethyl group more lipophilic than a methyl group? Partition coefficients and selected chemical shifts of aliphatic alcohols and trifluoroalcohols

Octanol-water partition coefficients were determined for 12 trifluoromethylated aliphatic alcohols and their unfluorinated counterparts. The latter values were derived from measurements using the benzyl alcohol-water solvent system after developing an appropriate correlation equation. Incidentally, an empirical equation was found which allows the partition coefficient of an unsubstituted alcohol to be estimated given the molecular formula and boiling point. Trifluorination strongly enhances lipophilicity only when the trifluoromethyl group is in the alpha-position. The enhancement is barely measurable for the beta- and gamma-(trifluoromethyl) alcohols, while the delta- and epsilon-(trifluoromethyl) compounds are considerably more hydrophilic than their parent compounds. Chemical shift comparisons suggest that the changes in relative lipophilicity are controlled primarily by the inductive effect of the trifluoromethyl group on the acidity-basicity of the hydroxyl group. New synthetic procedures for obtaining some of the alcohols are presented.     

Potential of immobilized artificial membrane chromatography for lipophilicity determination of arylpropionic acid non-steroidal anti-inflammatory drugs

Molecular lipophilicity can be expressed by logP or more conveniently by logk, i.e. determined by the traditional shake-flask technique or by liquid chromatography. The logk of 11 arylpropionic non-steroidal anti-inflammatory drugs (NSAIDs) was determined at pH 7.4 of the eluent using two stationary phases i.e. octadecylsilane phase and an immobilized artificial membrane (IAM.PC.MG) packing. The chromatographic retention factors extrapolated to 100% aqueous phase (logk(wODS) and logk(wIAM)) were correlated with n-octanol/water lipophilicity parameters (logP) and with n-octanol/water partition coefficients corrected for ionization at pH 7.4 (logD7.4). In this series of compounds, significant linear correlations (r>0.94) between the chromatographic parameters (logk(wIAM)) and the reference lipophilicity data (logP and logD7.4) were described. Moreover, regression analysis between the lipophilicity parameters and some pharmacokinetic data for the drugs under study were performed. The logk(wIAM) parameter over n-octanol/water partition data seems to provide a good model to obtain lipophilicity parameters of arylpropionic acid NSAIDs for quantitative structure-activity relationships studies.     

Development of a Preformulation Lipophilicity Screen Utilizing a C-18-Derivatized Polystyrene-Divinylbenzene High-Performance Liquid Chromatographic (HPLC) Column

Alkane/water partition coefficients have been predicted from the retention times of solutes using a C-18-derivatized polystyrene-divinylbenzene HPLC column (Act-I). Several classes of compounds, with molecular weights from 78 to 379 and partition coefficients ranging over several orders of magnitude, were included in the present study. A high correlation coefficient (0.953) was obtained from log-log plots of alkane/water partition coefficient versus capacity factor. A poor correlation was observed for octanol/water partition coefficients, presumably due to the hydrogen-bonding capability of octanol. The alkane/water correlation suggests that the system is devoid of significant specific solute-stationary phase interactions which are known to impart anomalous retention behavior to traditional reverse phase columns. Deviations of calculated alkane/water partition coefficients (and Hansch II_alkane coefficients) from observed values could not be explained in terms of solute (or substituent) polarizability, dipole moment, -para, or pK _HB values, further suggesting that specific interactions between the stationary phase and the solute are not significant. A molecular weight dependence that was independent of lipophilicity was observed. Thermodynamic and extrathermodynamic parameters of retention were obtained in order to investigate retention mechanisms for the Act-I column. The molecular weight dependence does not appear to be due to size exclusion or entropic expulsion of the solute from the stationary phase. Hansch II substituent coefficients calculated from retention times were found to be similar for benzene and steroid derivatives. Thus, the Act-I column may be utilized as a rapid lipophilicity screen for drug candidates of similar molecular weight.     

Structure-hepatic disposition relationships for phenolic compounds.

Phenolic compounds are widely used in therapeutic, environmental, and industrial applications. The present work seeks to define the hepatic disposition of 11 phenolic compounds with varying lipophilicities and molecular weights. The hepatic disposition kinetics were studied in a once-through in situ rat liver perfusion preparation in order to avoid extra-hepatic metabolism and recirculation effects. The phenols were administered using the impulse-response technique and the time course of hepatic venous effluent concentration was examined by moments and a two-compartment dispersion model. While the extraction of the phenolic compounds was relatively independent of lipophilicity, the estimated permeability-surface area (PS) product for influx of solutes into the hepatocytes could be related to the compounds' octanol-buffer partition coefficients (log Papp). This log PS-logPapp relationship was consistent with that reported earlier for another series of solutes with a wide range of lipophilicity. The metabolites produced from each of the phenolic compounds used in this study had mean transit times similar to those of their corresponding parent phenols, suggesting that the metabolites were not trapped in the liver as a consequence of their higher polarity. It is concluded that the strong solute lipophilicity-toxicity and lipophilicity-skin penetration relationships often seen for aqueous solutions of phenols are not evident for the hepatic extraction of these compounds. Such a conclusion is consistent with the hepatic extraction of phenolic compounds being mainly determined by a blood flow limitation in delivery of the phenol to the liver, rather than the intrinsic liver metabolic enzyme activities at the doses injected.     

The effect of lipophilicity of spin-labeled compounds on their distribution in solid lipid nanoparticle dispersions studied by electron paramagnetic resonance

Solid lipid nanoparticles (SLN) constitute an attractive drug carrier system. The aim of this study was to investigate the influence of lipophilicity and structure of different model molecules on their distribution in SLN dispersions. SLN composed of glyceryl tripalmitate as lipid and soybean lecithin and poloxamer 188 as stabilizers were prepared by a melt-emulsification process. PC(10,3), MeFASL(10,3), C(14)-Tempo, and Tempol were incorporated into SLN as spin-labeled compounds. The partition of SP between triglyceride and water was determined experimentally by electron paramagnetic resonance (EPR) and compared with calculated partition coefficients. The distribution of molecules in SLN dispersions was determined from the parameters of EPR spectra, from the reduction kinetics of the spin-labeled compounds with sodium ascorbate, and by computer simulation of EPR spectral line shapes. The experimentally obtained partition coefficients increase in the order Tempol < MeFASL(10,3) < C(14)-Tempo, showing the same trend as the partition coefficients calculated according to Rekker. In SLN dispersions, it was estimated that the ratio of SP between solid lipid core, phospholipid layers (deeper in SLN layer or in liposomes and closer to the surface of SLN), and water is for Tempol 0:0:100, for C(14)-Tempo 46:54(20:34):0, for MeFASL(10,3) 34:65(38:27):1, and for PC(10,3) 10:89(26:3:60):1.     

Ionization, lipophilicity and solubility properties of repaglinide

Potentiometric and spectrophotometric titrations were used for the determination of ionization behaviour, lipophilicity and solubility profile of repaglinide. Acid-base equilibria were characterized by means of protonation macro- and microconstants using Target Factor Analysis of spectrophotometric data. Lipophilicity profiles were evaluated by determination of partition coefficients of neutral and ionized forms of repaglinide in biphasic octanol/water system. The intrinsic solubilities of repaglinide were determined from the solubility data and temperature dependence of intrinsic solubilities were evaluated using van't Hoff equation. Repaglinide possesses two protonation sites and in aqueous solutions exhibits ampholitic properties. At isoelectric pH the zwitterionic form of the molecule predominates over the uncharged form with the tautomeric ratio, logKz=1.9. The difference between calculated and measured logP values, as well as the difference between logP values of uncharged form of repaglinide, HR0, and either one of mono-charged forms indicated the significant partition of zwitterion into octanol. Temperature dependence of solubility data revealed exothermic dissolution process with DeltasolH=-36 kJmol-1 and negative entropy of solution of DeltasolS=-0.19 kJK-1mol-1.     

The Influence of Peptide Structure on Transport Across Caco-2 Cells

The relationship between structure and permeability of peptides across epithelial cells was studied. Using confluent monolayers of Caco-2 cells as a model of the intestinal epithelium, permeability coefficients were obtained from the steady-state flux of a series of neutral and zwitterionic peptides prepared from D-phenylalanine and glycine. Although these peptides ranged in lipophilicity (log octanol/water partition coefficient) from –2.2 to +2.8, no correlation was found between the observed flux and the apparent lipophilicity. However, a strong correlation was found for the flux of the neutral series and the total number of hydrogen bonds the peptide could potentially make with water. These results suggest that a major impediment to peptide passive absorption is the energy required to break water–peptide hydrogen bonds in order for the solute to enter the cell membrane. This energy appears not to be offset by the favorable introduction of lipophilic side chains in the amino acid residues.     

Quantitative structure-anticonvulsant activity relationships of valproic acid, related carboxylic acids and tetrazoles

Valproic acid and several structurally related carboxylic acids and tetrazole analogues have been shown to antagonize seizures induced by pentylenetetrazole in mice. To investigate the influence of the alkyl substituents on the anticonvulsant activity, the octanol-water partition coefficients and relative pKa values were determined. Within the series of active carboxylic acids, there was a good correlation between the anticonvulsant activity and the partition coefficient (r = 0.86). The influence of pKa on the anticonvulsant activity was small but of statistical significance. When the most active compound, 5-heptyltetrazole was added to the carboxylic acid series, a low correlation between the anticonvulsant activity and a linear combination of lipophilicity and pKa resulted. The effect of the polar moieties in alkyl-substituted anticonvulsant compounds was assessed by comparison of the regression equations with either an added pKa or dipole moment term to the term for lipophilicity. It appears that other factors, such as the nature of the alkyl substituent, influence the anticonvulsant activity. The inactivity of the cyclohexylmethyl-substituted compounds, cyclohexylacetic acid and 5-cyclohexylmethyltetrazole may be due to subtle steric effects at a critical step, either involving oxidative metabolism or an interaction at an active site.     

Correlation of physicochemical properties with absorption and metabolism of some tricyclic drugs

Octanol and dodecane partition coefficients, surface activity and adsorbability to activated charcoal were determined for six tricyclic psychotropic drugs with N-dimethylalkyl side chains. Surface activity correlated well with the partition coefficients, and all drugs obeyed the Langmuir adsorption isotherm. A correlation between the reciprocal of the death time of gold fish exposed to drugs and partition coefficients was observed. The extent to which the drugs were N-demethylated as measured by formaldehyde formed in rat liver homogenate incubations correlated with their adsorbability to activated charcoal but not with their ability to inhibit aniline-p-hydroxylase, nor was there a linear correspondence between N-demethylation and drug lipophilicity as indicated by partition coefficients or surface activity.     

Comparison between immobilized artificial membrane (IAM) HPLC data and lipophilicity in n-octanol for quinolone antibacterial agents

The membrane phospholipid affinity of ten quinolone antibacterial agents, including both acidic and zwitterionic compounds, was measured by HPLC on two different immobilized artificial membrane (IAM) stationary phases, namely IAM.PC.MG and IAM.PC.DD2; it is expressed as the logarithm of the retention factor measured with (or extrapolated to) 100% aqueous eluent at pH 7.0, .

Quinolones are a class of highly potent, orally active, broad-spectrum antibacterial agents. For these compounds, lipophilicity values in n-octanol found in the literature, either calculated or measured, are not consistent with each other and are too low to be compatible with their pharmacokinetic properties.

The values obtained in this study showed no relation with any of the lipophilicity values in the literature (clog P(a), clog P(b), MLP, log D^7.4). In contrast, they were collinear with a new lipophilicity scale we had previously obtained by an original ion-pair reversed-phase HPLC method set up to estimate the lipophilicity of the neutral forms, log P^N. Moreover, when comparing the retention of quinolones on IAM to the retention of structurally unrelated neutral compounds, we observed that they interact with phospholipids with the same affinity as neutral isolipophilic compounds.

The use of an eluent at pH 5.5, instead of pH 7.0, increased the retention on IAM not only for acidic, but also for zwitterionic congeners, indicating that phospholipid affinity is enhanced in the experimental conditions that depress the ionization of the acidic function, even when the ionization of the amino function increases simultaneously.

To gain an insight into the mechanism of quinolones/serum-protein interactions, we investigated about possible relationships between quinolones affinity data for serum proteins and IAM data. Quinolone affinity for both HSA and AGP was already demonstrated poorly related to n-octanol lipophilicity values, probably due to the occurrence of electrostatic interactions. Only poor relationships were found between IAM and HSA affinity data, whereas quite good relationships were found with AGP affinity data. However, IAM.PC.DD2 data correlated better than those on IAM.PC.MG with quinolone affinity for both serum-proteins, mainly due to the fact that IAM.PC.MG phase is scarcely discriminative for the compounds with the highest retention values.

The results suggest that IAM retention can produce a lipophilicity scale that, unlike solvent/water partition coefficients, is consistent with the pharmacokinetic behaviour of zwitterionic quinolones.     

Quantitative structure-metabolism relationship analyses of MAO-mediated toxication of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analogues.

The 1-octanol/water partition coefficients of a number of toxic and nontoxic analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were determined using centrifugal partition chromatography (CPC), a novel and effective technique for measuring lipophilicity, and found to be highly correlated with values calculated by a fragmental method. Some conformational properties of these compounds were also assessed by molecular mechanics calculations and 1H-NMR spectroscopy. A quantitative structure-metabolism relationship (QSMR) study of MPTP and analogues based on literature data was undertaken in order to determine the key features eliciting MAO-A and MAO-B reactivity and selectivity and influencing toxication. Multiple regression analysis (MRA) and comparative molecular field analysis (CoMFA) showed that MAO-B activity is nonlinearly (parabolically or bilinearly) correlated to the lipophilicity of MPTP analogues and influenced negatively by steric effects exerted by bulky substituents in the ortho position. With regard to MAO-A activity, while lipophilicity was shown to play no relevant role, electrostatic and steric fields led to a 3D-QSAR model with an acceptable predictive value (cross-validated r2 = 0.571). The results of this study bring evidence at a quantitative level that the MAO-B and MAO-A catalytic sites differ in their hydrophobic, steric, and stereoelectronic requirements.     

Investigation of N-hydroxythalidomide in vitro stability and comparison to other N-substituted derivatives

The stability of N-substituted derivatives of thalidomide was studied and compared to that of thalidomide itself. Nitrogen atom included in glutarimide ring was successively substituted by a hydroxy group, a methyl acetate group, and an ethyl group. Lipophilicities of these compounds were determined using the method based on experimental determinations of partition coefficients developed by Hansch. Hydroxy group led to a decrease of lipophilicity. Substitution of the nitrogen atom by an ethyl group or a methyl acetate group allowed an increase of lipophilicity. Relative stabilities of each compound were determined under physiological conditions: pH (7.4) and temperature (37 degrees C) using high performance liquid chromatography procedure. The program Sigma Plot was used to fit experimental data in order to obtain the half-lifes of thalidomide and its analogs. In the case of substitution by an ethyl group, the increase of lipophilicity (Delta log P = 0.36) was in agreement with a higher stability in aqueous medium. In the case of methyl acetate group, hydrolysis of the cycle was chemically favoured despite a higher lipophilicity compared to those of thalidomide. In the case of N-hydroxy compound, the decrease in lipophilicity was not sufficient to affect the stability.     

Correlation of the octanol/water partition coefficient with clearance half-times of intratracheally instilled aromatic hydrocarbons in rats

Studies on the lung retention of polycyclic aromatic hydrocarbons (PAH) after inhalation have indicated that, in general, the PAH are rapidly cleared from the respiratory tract. Clearance of the PAH from the lungs is best described as bi-phasic, with the long-term component of the clearance curve having a half-time of greater than 24 h. The purpose of this study was to determine whether a relationship exists between the lipophilicity (as measured by the octanol/water partition coefficient, P) of various PAH and the short-term and long-term clearance half-times of PAH in rat lungs. Female F344/Crl rats were administered intratracheally 1 nmol of 14C-labelled anthracene (AN), benz[a]anthracene (BA), 1-nitropyrene (NP), 6-nitrobenzo[a]pyrene (6-NBP), or dibenzo[c,g]carbazole (DBC). At various times after instillation rats were sacrificed and the amount of 14C remaining in the lungs was determined. Octanol/water partition coefficients were experimentally determined for each of the PAH used. Clearance of 14C from rat lungs following instillation of the different PAH was biphasic. In all cases, greater than 85% of the initial dose instilled was cleared with a half-time of less than 1 h. The half-times for clearance of the residual 14C (1-15% of the dose) were 26, 30, 36, 53 and 63 h for AN, NP, 6-NBP, BA and DBC, respectively. The log of the octanol/water partition coefficients for the different PAH examined ranged from 4.1 (AN) to 6.05 (DBC). Plots of the octanol/water coefficients vs. the long-term clearance half-time for the PAH indicated a linear correlation (p less than 0.001; r2 = 0.96). The results from this study indicate that the greater the lipophilicity of the PAH, the slower the long-term clearance of a small fraction (1-15%) of PAH from rat lungs. These data suggest that predictions of long-term lung clearance can be made for PAH with log octanol/water partition coefficients between 4 and 6.     

Protonation equilibrium and lipophilicity of olamufloxacin (HSR-903), a newly synthesized fluoroquinolone antibacterial.

This study was performed to characterize the protonation equilibrium at the molecular level and pH-dependent lipophilicity of olamufloxacin. The deprotonation fraction of the carboxyl group as a function of pH was specifically calculated at the critical wavelength 294 nm, where UV pH-dependent absorbance of olamufloxacin was independent of the ionized state of the aminopyrrolidinyl amino group but heavily depended on that of the carboxyl moiety. Accordingly, micro-protonation equilibrium could be described using a nonlinear least-squares regression program MULTI. In contrast, macro-protonation equilibrium was depicted at most wavelengths where olamufloxacin absorbance was influenced by ionized states of both proton-binding groups, results coinciding with the former. Furthermore, distribution features of four microspecies in aqueous phase were assessed. The apparent partition coefficient versus pH profile of olamufloxacin showed a parabolic curve in n-octanol/buffer system which reached peak near pH 8, agreeing with the above determined isoelectric point (pI). Ion-pair effect was observed for olamufloxacin under an acidic condition, eliciting experimental values higher than those theoretically calculated, which was similar to ciprofloxacin but not levofloxacin due to amino group type. Moreover, olamufloxacin was moderately lipophilic in comparison with other quinolones, with an apparent partition coefficient of 1.95 at pH 7.4.