INVESTIGATION OF POLAR SURFACE AREA AS A NOVEL PARAMETER AFFECTING ORAL BIOAVAILABILITY OF DRUGS

Fast and reliable prediction of intestinal absorption is a key factor in drug design. New
parameters for this prediction have been introduced recently. These included the hydrogen
bonding capacity and the polar surface area (PSA). High PSA accounted for poor oral
absorption and vice versa. Here we are investigating the significance of PSA in intestinal
absorption of a series of lipophilic steroidal model drugs. These included; Betamethason
valerate (BMV), Betamethasone (BM), prednisone (PD) and methyltestosterone (MT), with PSA
values of 100.9, 94.83, 91.67 and 37.3 Å, respectively. An in situ intestinal perfusion technique
was employed using the rabbit as model animal. The study investigated drug absorption from
the jejunoileum and ascending colon. The results revealed good absorption from both segments
for all tested drugs except PD which was absorbed from the jejunoileum only. Poor correlation
was evident between the absorptive clearance and the net water flux in both segments
suggesting mainly a trans-cellular absorption of these compounds. The percentage fraction
absorbed (%Fa) was in the order of BMV > MT > BM > PD with the later showing negligible
absorption from the ascending colon. These results did not correlate with the calculated PSA
values. Accordingly, the octanol/water partition coefficient (log P) was considered. The log P
values were, 3.6, 3.36, 1.94 and 1.46 for BMV, MT, BM and PD, respectively. These values
correlated with the %Fa values. However, it should be noted that the recorded colonic
absorption is against expectation for such lipophilic drugs. In conclusion PSA failed to correlate with the oral absorption of the lipophilic steroids. Although log P correlated well with
the absorption of these compounds especially with jejunoileum segment it is advisable not to
rely on single factor for predicting oral bioavailability.