Pathways of paracetamol absorption from layered excipient suppositories: artificial intelligence approach

When studying paracetamol availability after rectal administration, the differences between slower and faster release suppositories were discovered. Approach with modelling and simulation of compartment-based models was used to explore the differences. A study of paracetamol from layered excipient suppositories shows that many different mechanisms are involved in the drug pharmacokinetics. There is also a large number of articles, each dealing with only one or with a few of the mechanisms. However, there is little information available on how the mechanisms interact in the organism and thus govern the pharmacokinetics of the drug, which means that systemic view in the expert knowledge is missing. In the case of paracetamol rectal availability the use of partially fuzzyfied model allowed systemic combination of all described mechanisms found in the literature and measured data. In spite of non-identifiability, the model showed that patterns that explained differences in bioavailabilities of the two formulations of suppositories could be found. Results of modelling and simulation show that "in vivo" there is practically no difference in cumulative release profiles between the two formulations. However, due to higher content of mono-di-glycerides in a slower release formulation, the extent of absorption is augmented both by absorption-enhancing effect of mono-di-glycerides and the liver bypass mechanism via diminished viscosity.