Chaw, Cheng Shu; (1999) The gastric emptying and drug absorption from liquid formulations of 4-aminosalicylic acid. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The fate of a 500mg dose 4-aminosalicylic acid (4ASA) liquid formulation was investigated in humans. Buffered pH3 and 7 oral liquid formulations were designed to provide adequate evaluation of the gastric emptying using applied potential tomography (APT). The gastric luminal pH profiles were monitored using a pH-sensitive radiotelemetry capsule and blood was sampled over 8 hours. In a further series of experiments, the gastric luminal acid secretion was restricted by ranitidine pre-treatment, to test the performance of APT and to observe the influence on the absorption profile of 4ASA. The content of 4ASA and its metabolites in the blood were analysed by HPLC assay. An intravenous administration of 4ASA was used as a reference to calculate the pharmacokinetic profiles with a deconvolution technique based on maximum entropy theory and a mass balance technique based on Wagner-Nelson compartmental theory. The gastric emptying parameters were determined using statistical moments to provide a mean gastric residence time. The results showed that the performance of APT was not affected by physiological acid secretion. The ranitidine pre-treatment gave a full acid suppression until after the gastric emptying process of the oral liquid was completed. The shape of the blood level curves of 4ASA liquid formulations was influenced by the gastric emptying rate, which in turn was controlled by the duodenum acid feedback mechanism. The gastric emptying rate of pH3 4ASA formulation was delayed and hence an extended 4ASA mean absorption time was observed. The elimination rate of 4ASA was rapid when compared to its major metabolite, N-acetyl-4ASA (AASA). The bioavailability of 4ASA and AASA of the different formulations was restricted, with a mean average value ranging from 61 to 85% depending on treatment. The results derived from the maximum entropy approach differed from those of the Wagner- Nelson method. The limited intravenous data points restricted the calculations. The 4ASA absorption rate distribution profiles, calculated using the maximum entropy approach, in some cases displayed a double peak phenomenon, which demonstrated the complexity in disposition even for of a simple oral liquid formulation of 4ASA. This phenomenon was not observed with the Wagner-Nelson method. The clearance and rate constant values of the current study differed from previous reported cases, where much higher doses and different dosage forms had been used.

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