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Notes: Abstract Previous data on salicylamide (SAM) metabolism in the perfused rat liver had indicated that SAM was metabolized by three parallel (competing) pathways: sulfation, glucuronidation, and hydroxylation, whereas sequential metabolism of the hydroxylated metabolite, gentisamide (GAM), was solely via 5-glucuronidation to form GAM-5G. However, under comparable conditions, preformed GAM formed mainly two monosulfate conjugates at the 2- and 5-positions (GAM-2S and GAM-5S); 5-glucuronidation was a minor pathway. In the present study, the techniques of normal (N) and retrograde (R) rat liver perfusion with SAM and mathematic modeling on SAM and GAM metabolism were used to explore the role of enzymic distributions in determining the dissimilar fates of GAM, as a generated metabolite of SAM or as preformed GAM. Changes in the steady-state extraction ratio of SAM (E) and metabolite formation ratios between N and R perfusions were used as indices of the uneven distribution of enzyme activities. Two SAM concentrations (134 and 295 μM) were used for single-pass perfusion: the lower SAM concentration exceeded the apparent Km for SAM sulfation but was less than those for SAM glucuronidation and hydroxylation; the higher concentration exceeded the apparent Km 's for SAM sulfation and glucuronidation but was less than the Km for hydroxylation. Simulation of SAM metabolism data was carried out with various enzyme distribution patterns and extended to include GAM metabolism. At both input concentrations, E washigh (0.94 at 134 μMand 0.7 at 295 μM) and unchanged during N and R, with SAM-sulfate (SAM-S) as the major metabolite and GAM-5G as the only detectable metabolite of GAM. Saturation of SAM sulfation occurred at the higher input SAM concentration as shown by a decrease in Eand a proportionally less increase in sulfation rates and proportionally more than expected increases in SAM hydroxylation and glucuronidation rates. At both SAM concentrations, the steady-state ratio of metabolite formation rates for SAM-S/SAM-G decreased when flow direction changed from N to R. An insignificant decrease in SAM-S/SAM-OH was observed at the low input SAM concentration, due to the small amount of SAM-OH formed and hence large variation in the ratio among the preparations, whereas at the high input SAM concentration, the decrease in SAM-S/SAM-OH with a change in flow direction from N to R was evident. The metabolite formation ratio, SAM-G/SAM-OH, however, was unchanged at both input concentrations and flow directions. The observed data suggest an anterior SAM sulfation system in relation to the glucuronidation and hydroxylation systems, which are distributed similarly. When the observations were compared to predictions from the enzyme-distributed models, the best prediction on SAM metabolism was given by a model which described sulfation activities anteriorly, glucuronidation activities evenly, and hydroxylation activities posteriorly (perivenous). When the model was used to predict data for SAM and GAM metabolism in once-through perfused rat livers at different input SAM concentrations, in the absence or presence of the sulfation inhibitor, 2,6-dichloro-4-nitrophenol (DCNP), the predictions were in close agreement with previously observed SAM data but failed to predict the exclusive formation of GAM-SG; rather, GAM-2S and GAM-5S were predicted as major sequential metabolites of SAM. The poor correlation for GAM metabolic data may be explained on the basis of subcellular enzyme localizations: the cytochromes P-450 and UDP-glucuronyltransferases, being membrane-bound enzymes, are more coupled for GAM formation and glucuronidation, when GAM was generated intracellularly. The present study suggests that subcompartmentalization of enzymes may need to be considered in hepatic modeling for better prediction of metabolic events.

Notes: Abstract An erodible association polymer system based on blends of cellulose acetate phthalate (CAP) and Pluronic F127, a block copolymer of poly(ethylene oxide) and poly(propylene oxide), has been investigated for its applicability to rate-programmed drug delivery. The compatibility and thermal properties were characterized by DSC and FTIR. Results from the thermal analysis indicate that the blends are compatible above 50% CAP, as revealed by a single composition-dependent glass transition temperature (T g). The existence of molecular association through intermolecular hydrogen bonding between the carboxylic acid and the ether oxygen groups is supported by the observation of an upward shift in the IR carbonyl stretching frequency at increasing Pluronic F127 concentrations. Using theophylline as a model drug, the in vitro polymer erosion and drug release characteristics of the present polymer system were evaluated at different buffer pH's on a rotating-disk apparatus. The results show that the rates of both polymer erosion and drug release increase with the Pluronic F127 concentration in the blend. Further, at pH 4, the polymer erosion is minimal and the theophylline release appears to be governed mainly by diffusion through the polymer matrix. In contrast, at pH 7.4, the theophylline release is controlled primarily by the polymer surface erosion. To demonstrate the unique approach to programmed drug release based on the concept of non-uniform initial drug distribution, pulsatile patterns of drug release have been achieved successfully from the present surface-erodible polymer system using a multilaminate sample design with alternating drug-loaded layers. The results suggest that the pulsing frequency and peak rate of such pulsatile drug delivery are pH dependent; however, they can be modulated by varying the thickness, drug loading, and erosion rate of the constituent layers in the multilaminate.