FIGURE 5 Log D profile of a zwitter ion (base), p/Ca (base) = 5.6, and p/Ca (acid) = 7.0.
value (3-4) but once we reach in the range of 4 to 7, we risk accumulation of drug I in the body fat that can prove toxic due to accumulation of drug in multiple dosing situations. The renal clearance of drugs with log D (measured at pH 7.4) above zero will decrease renal clearance and increase metabolic clearance; the pKa of drugs also plays an important role here as highly ionized drugs are kept out of cells and thus out of systemic toxicity; generally, a pKa of 6to8 will be most optimal for transport across various biologic membranes.
When making a choice, generally a drug with lowest log P will be desirable; however, that may require making a choice between a high- versus a low-molecular weight molecule; it is known that high-molecular weight drugs are generally more allergenic. The goal should be to achieve a minimum hydrophobicity using a combination of log P, pKa and molecular size. The principle of minimum hydrophobicity keeps the drugs out of central nervous system that may produce side effects like depression, etc., which means that most molecules should have a log P lower than 2.0; this technique was used in the design of the newer generation of non-sedative
antihistamines. Avery high lipophilicity should also be avoided because of adverse effects on protein binding and drug absorption, including solubility.
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