Lipophilicity Descriptors Correlate Uniquely with Pharmacokinetic and Blood-Brain Barrier Penetration Parameters for Selected Antipsychotic Drugs

Lipophilicity is an important physicochemical parameter of biological relevance; although its in- vivo predictive capability is dependent on accuracy and reliability of platforms used for its determination. This work examines biomimetic attribute of isocratic chromatographic hydrophobicity index (ICHI), experimental logarithm of octanol ­ water partition coefficient (LogP) and some computed lipophilicity indices for eight (8) selected antipsychotic agents and their predictive capability in drug discovery. The retention behavior of 5 first-generation and 3 second-generation antipsychotics was determined on reversed-phase chromatographic platform using methanol-phosphate buffer (pH 6.8) mobile phase. The retardation factor obtained was transformed to Rm, and plotted against volume fraction of organic modifier in the mobile phase to generate linear graph whose x- intercept is ICHI. Experimental LogP values were curled from literature while computed LogP were obtained using respective software. The experimentally determined LogPoctanol/water and ICHI were first correlated with index of brain permeability (BBB); before all lipophilicity indices were comparatively evaluated and correlated with in-vivo-normalized pharmacokinetic parameters curled from literature. ICHI gave better correlation with BBB index (r = 0.976) compared to Log Poctanol/water (r = 0.557). Comparative lipophilicity evaluation shows clustered pattern for second generation antipsychotics compared to first generation. In vivo correlation was poorer for the 8 drugs (r < 0.7), better with subset of phenothiazine homologues (r = 0.51 to 0.97). The ALogP, LogPoctanol/water, cLogP and ICHI gave highest correlation with the pharmacokinetic parameters. The biomimetic attributes of ICHI is better than for LogPoctanol/water in predicting brain permeability, but lower for in-vivo pharmacokinetic prediction.

Evaluation of Dimethylformamide (DMF) as an Organic Modifier in Hydrophobicity Index (R[m]) Determination

PURPOSE: Ideal behaviour of mixtures of organic modifier and water is reflected by a linear relationship between refractive index and fraction of organic modifier in the mixture. This study was carried out to investigate dimethylformamide (DMF) as an organic modifier in hydrophobicity index (Rm) determination. METHOD: We quantitatively evaluated the problem of partial miscibility of phases associated with the reversed phase thin layer chromatographic (RPTLC) system; using liquid paraffin as stationary phase and acetone/water mixtures as mobile phase. Ideality of behaviour of acetone/water mixtures was investigated by refractive index measurements. R[m] values of compounds were determined using mixtures of acetone and water as mobile phase. RESULTS: DMF/water mixture behaved ideally across the whole concentration range investigated (0-100 percent) while acetone/water mixture deviated from ideal behaviour when the concentration of acetone in the mixture was 80 percent. DMF also gave a better extrapolation of R[m] value from linear regression of partition data than acetone for bezafibrate used as a test-drug molecule. CONCLUSION : DMF is a better organic modifier than acetone in this RPTLC system. These findings could be extended to drug-receptor and drug design studies. The use of dimethylformamide (DMF) in preference to acetone as organic modifier is proposed in this study