Semi-mechanistic PK/PD modeling of Paracetamol and Sulfapyridine to characterize pharmacological effects on gastric emptying and small intestinal transit.
(English)Manuscript (preprint) (Other academic)
The paracetamol (PCM) and sulfapyridine (SP) double marker technique is based on combined gastric administration of PCM and sulfasalazine followed by plasma concentration measurements for PCM and SP. PCM is rapidly absorbed from the duodenum and can be regarded as a marker for gastric emptying (GE). Sulfasalazine is poorly absorbed from the small intestine but is extensively metabolized in the colon by bacteria into SP. As SP is only absorbed from the colon it serves as a marker for small intestinal transit time (SITT). The double marker method is used to identify and characterize effects on GE and SITT. The aim of the present investigation was to demonstrate how semi-mechanistic modeling of PCM and SP could facilitate characterization and the understanding of pharmacologically induced changes in GI transit under fed and fasting conditions. Two double marker validation studies were performed in dogs with erythromycin (1 mg/kg) and atropine (0.06 mg/kg), both of which have been described to affect GE and SITT. A semi-mechanistic nonlinear mixed-effects model was applied for simultaneous analysis of PCM and SP plasma concentrations. The model featured a compartment representing the stomach linked to a colon compartment via a series of four transit compartments representing the small intestine. Disposition of PCM and SP was described with standard 2- and 1-compartment models respectively. An essential part of the model was the inclusion of saturable first pass metabolism of PCM. This has been described before, but never taken into account when using PCM as a marker for GE. The effect of concomitant food intake on GE and SITT was found to be time dependent. Atropine and erythromycin were found to have time/concentration dependent effects on GE and SITT. As expected, erythromycin stimulated and atropine inhibited GE in the fasting state. Given the saturable first pass metabolism this resulted in almost twice as high bioavailability for PCM in erythromycin treated dogs (90%) as in atropine treated dogs (50%). Atropine treatment was primarily found to counteract the stimulatory effect of food intake on SITT, whereas erythromycin prolonged SITT under both fed and fasting conditions. Simultaneous modeling of PCM and SP was found to increase mechanistic understanding and result in plausible estimates of GE and SITT.
gastric emptying, small intestinal transit, mechanistic modeling, NONMEM
Research subject Pharmacokinetics and Drug Therapy
IdentifiersURN: urn:nbn:se:uu:diva-149313OAI: oai:DiVA.org:uu-149313DiVA: diva2:404477