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Figure 4sPlot showing inverse relationship between flux and skin cytosolic
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extent in the cytosol than those made with (R)-2-phenyl-
butyryl chloride. This assumes significance in light of the
fact that the S isomer of propranolol is 100 times more
potent than the R isomer. These prodrugs being more
efficient at avoiding metabolism further help in improving
the skin permeation of propranolol.
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In Figure 3, the cumulative amount of propranolol and
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and regenerated propranolol) transported through the full
thickness rat skin was plotted against time. It appears that
all four drugs impart increase in lipophilicity as compared
to parent PL as indicated by their PC data. The hydrolysis
data in conjunction with the flux data clearly suggests that
the prodrug, which has optimum stratum corneum parti-
tioning and exhibits the most resistance to enzymatic
hydrolysis, is able to cause the highest permeation. As
shown (Figure 4), the transdermal fluxes may be inversely
related to their skin cytosolic enzymatic rate constants.
Therefore, a design of prodrugs should not only involve
optimization of physicochemical parameters, i.e., lipophi-
licity and aqueous solubility, but must also include opti-
mum evaluation of biochemical stability by membranes
containing degradative enzymes.
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Journal of Pharmaceutical Sciences / 549
Vol. 88, No. 5, May 1999