Investigation of Low Bioavailability Using Physiologically Based Pharmacokinetic Modeling: A Case Example (Lassbio-596)
Manuela de Lima Toccafondo Vieira
National Institute of Science and Technology of Drugs and Medicines, Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio®), Federal University Federal of Rio de Janeiro, CCS, Cidade Universitária, P.O. Box 68006, ZIP: 21941-971, Rio de Janeiro-RJ, Brazil and Departament of Clinical Analysis and Toxicological, Laboratory of Experimental Toxicology, School of Pharmacy, Federal University Federal of Minas Gerais, Av. Antônio Carlos, 6627, Pampulha, ZIP: 31270-901, Belo Horizonte-MG, Brazil.
Lídia Moreira Lima
National Institute of Science and Technology of Drugs and Medicines, Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio®), Federal University Federal of Rio de Janeiro, CCS, Cidade Universitária, P.O. Box 68006, ZIP: 21941-971, Rio de Janeiro-RJ, Brazil
Eliezer J. Barreiro
National Institute of Science and Technology of Drugs and Medicines, Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio®), Federal University Federal of Rio de Janeiro, CCS, Cidade Universitária, P.O. Box 68006, ZIP: 21941-971, Rio de Janeiro-RJ, Brazil
Carlos Alberto Tagliati *
National Institute of Science and Technology of Drugs and Medicines, Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio®), Federal University Federal of Rio de Janeiro, CCS, Cidade Universitária, P.O. Box 68006, ZIP: 21941-971, Rio de Janeiro-RJ, Brazil Departament of Clinical Analysis and Toxicological, Laboratory of Experimental Toxicology, School of Pharmacy, Federal University Federal of Minas Gerais, Av. Antônio Carlos, 6627, Pampulha, ZIP: 31270-901, Belo Horizonte-MG, Brazil.
*Author to whom correspondence should be addressed.
Abstract
Aim: Investigate the possible mechanism (s) of the poor bioavailability of a lipophilic compound in rats using the physiologically based pharmacokinetic (PBPK) modeling approach.
Methodology: A rat PBPK model was constructed using data from intravenous administration, and verified by comparing predicted tissue concentrations (kidneys, liver and lungs) with experimental data from tissue distribution studies. Using parameter sensitivity analysis, the model was used to investigate the absorption characteristics of the compound and the probable causes of the low absorbed fraction.
Results: Sensitivity analysis of absorption parameters was performed to understand the absorption characteristic of the compound in regard to permeability, solubility and intra-gut degradation. Taking in consideration the latter factor, the oral pharmacokinetics of the tested compound was satisfactorily predicted in rats.
Conclusion: The PBPK simulation results suggest that chemical or/and bacterial degradation of the compound in the gastrointestinal tract may be a probable cause of the low bioavailability observed.
Keywords: Physiologically-based pharmacokinetic, pharmacokinetic, bioavailability, modeling