Physicochemical Properties Governing Drug Penetration Into The

Carrier-independent penetration of antibiotics and other drugs into the eye (11,16,23,63,81), like that at other anatomical sites (16,23,53,63,66), is related to the physicochemical properties of the compound, which include lipophilicity and molecular weight/size and protein binding. The effects of these independent variables on drug penetration into bacteria (96) and into different anatomical compartments have been investigated by several laboratories (35,40,52,66,80,97). Multiple linear regression analysis shows that the logarithm of the penetration of compounds across planar lipid bilayers and tissue membranes correlates with the oil/water partition ratio, the inverse of the square root of the molecular weight (8) and the free fraction of drug (24,53,63). Almost all studies show that the oil/water partition ratio (lipophilicity) is generally the most predictive variable of drug transport into and out of privileged anatomical spaces (Fig. 1).

In relation to ocular drug penetration following systemic administration, only the unbound fraction of drug is in diffusional exchange across the blood-ocular barriers. In principle, protein binding can and should be included in dose determination. Thus, true comparison of drug penetration should be on the basis of the unbound fraction in the plasma, so that binding does not enter as a factor into the ocular kinetics. However, as

Figure 1 Relationship between the quinolone partition coefficients and levels of drug penetration into the vitreous humor following systemic drug administration, and elimination rate half-lives following direct intravitreal injection. The only statistically significant (when examined univariately; multiple linear regression did not improve model fits) quinolone physicochemical property related to ocular drug translocation was lipophilicity. The partition coefficients for direct and systemic drug administration are shown on the top and bottom abscissas, respectively.

Figure 1 Relationship between the quinolone partition coefficients and levels of drug penetration into the vitreous humor following systemic drug administration, and elimination rate half-lives following direct intravitreal injection. The only statistically significant (when examined univariately; multiple linear regression did not improve model fits) quinolone physicochemical property related to ocular drug translocation was lipophilicity. The partition coefficients for direct and systemic drug administration are shown on the top and bottom abscissas, respectively.

already noted, many factors influence drug entry into protected compartments, and ceftriaxone, which is >95% protein bound, penetrates into the CSF better than other, less protein-bound cephalosporins. Since intracam-eral penetration is inversely related to molecular weight/size, drugs with a large molecular weight are likely to be excluded from aqueous and vitreous humors after systemic administration, similar to blood proteins and macro-molecules. However, compounds may cross the blood-ocular barriers in spite of their large molecular size, and the rate of penetration is correlated with their lipid solubility, as expressed by their oil/water partition ratio. Unfortunately, the ability to further delineate the relationship between lipo-phility and molecular size/weight is curtailed due to the limit molecular weight/size within families of chemotherapeutic compounds.

Independent studies (52,66) have demonstrated the correlation between lipophilicity and penetration into or elimination from the eye following systemic (17,45,52,73,74) or intravitreal injection (33-35,65) in non-pigmented, uninfected rabbits (42,78). A similar relationship between lipophilicity, penetration, and efflux occurs in prokaryotes [96].

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