The relationship between nutritional status and pharmacokinetics has been previously studied for classical anticancer drugs, but this relationship remains unexplored for modern therapies involving targeted drugs and new administration routes. In this context, the main objective of this thesis was to evaluate, in undernourished and well-nourished Wistar rats, the impact of undernourishment on the pharmacokinetics of erlotinib and gefitinib, two novel orally administered targeted-drugs. The research investigation was divided into three main experiments: • Evaluation of analytical and molecular alterations associated with undernourishment • In situ intestinal perfusion studies • In vivo pharmacokinetics studies This Doctoral Thesis yielded the following conclusions: 1. Undernourishment causes significant alterations on mRNA expression levels of intestinal and hepatic metabolic enzymes (Cyp1A1, Cyp1A2 and UDP) and transporter proteins (OATP, MRP2 and P-gp). In liver tissue, mRNA levels of all the quantified metabolic enzymes, except for cytochromes, were diminished in undernourishment status. On the other side, alterations of mRNA levels in intestinal tissue do not follow a particular trend and the final outcome is dependent on the assayed intestinal segment and on the evaluated enzyme. 2. The observed alterations in alanine-aminotransferase and aspartate-aminotransferase hepatic enzymes, along with the reduction of albumin plasmatic concentration, confirm the occurrence of hepatic damage as a result of undernourishment status. Likewise, the decreased count of blood cells corroborates bone-marrow dysfunction under protein-energy under-nutrition. 3. A passive diffusion uptake process and an active secretion process control erlotinib intestinal absorption through both of the assayed intestinal segments. This active secretion process is sensitive to nutritional status and to the presence of levofloxacin. 4. A passive diffusion uptake process governs gefitinib intestinal absorption, which proved not to be influenced by the addition of sodium azide to the perfusion solution. Furthermore, under this in situ assay conditions, alterations of gefitinib absorption process did not take place as a consequence of the nutritional status of rats. 5. A two-compartment model proved to describe best the pharmacokinetic profiles both for erlotinib and gefitinib. 6. A 5% decrease in erlotinib clearance takes place in undernourishment status. Drug bioavailability in magnitude (f) and rate (ka) are dependent on nutritional status and on the type of dispersion system employed for oral administration: • Bioavailability in magnitude is incomplete only when erlotinib suspension is administered to norm-nourished rats. • Absorption rate constant is 52% lower when erlotinib solution is administered in undernourished rats as compared to the administration in norm-nourished rats. These results yield an expected 20% higher area under the concentration-time curve for erlotinib in undernourished patients as compared with norm-nourished ones. 7. Volume of distribution and bioavailability parameters for gefitinib are increased 30 and 50%, respectively, in protein-energy undernourishment status. This preclinical results yield simulation outcomes, which indicate that minimum trough concentration and area under the concentration-time curve in undernourished patients are expected to be 50% higher when compared to norm-nourished patients. 8. The response of the organism to compensate the deficiencies generated by an inadequate energy and protein intake is very complex. Consequently, general pharmacokinetic changes in undernourishment status are very variable, difficult to predict and dependent on the evaluated drug, given that all LADME processes are sensitive to these alterations.

The relationship between nutritional status and pharmacokinetics has been previously studied for classical anticancer drugs, but this relationship remains unexplored for modern therapies involving targeted drugs and new administration routes. In this context, the main objective of this thesis was to evaluate, in undernourished and well-nourished Wistar rats, the impact of undernourishment on the pharmacokinetics of erlotinib and gefitinib, two novel orally administered targeted-drugs. The research investigation was divided into three main experiments: • Evaluation of analytical and molecular alterations associated with undernourishment • In situ intestinal perfusion studies • In vivo pharmacokinetics studies This Doctoral Thesis yielded the following conclusions: 1. Undernourishment causes significant alterations on mRNA expression levels of intestinal and hepatic metabolic enzymes (Cyp1A1, Cyp1A2 and UDP) and transporter proteins (OATP, MRP2 and P-gp). In liver tissue, mRNA levels of all the quantified metabolic enzymes, except for cytochromes, were diminished in undernourishment status. On the other side, alterations of mRNA levels in intestinal tissue do not follow a particular trend and the final outcome is dependent on the assayed intestinal segment and on the evaluated enzyme. 2. The observed alterations in alanine-aminotransferase and aspartate-aminotransferase hepatic enzymes, along with the reduction of albumin plasmatic concentration, confirm the occurrence of hepatic damage as a result of undernourishment status. Likewise, the decreased count of blood cells corroborates bone-marrow dysfunction under protein-energy under-nutrition. 3. A passive diffusion uptake process and an active secretion process control erlotinib intestinal absorption through both of the assayed intestinal segments. This active secretion process is sensitive to nutritional status and to the presence of levofloxacin. 4. A passive diffusion uptake process governs gefitinib intestinal absorption, which proved not to be influenced by the addition of sodium azide to the perfusion solution. Furthermore, under this in situ assay conditions, alterations of gefitinib absorption process did not take place as a consequence of the nutritional status of rats. 5. A two-compartment model proved to describe best the pharmacokinetic profiles both for erlotinib and gefitinib. 6. A 5% decrease in erlotinib clearance takes place in undernourishment status. Drug bioavailability in magnitude (f) and rate (ka) are dependent on nutritional status and on the type of dispersion system employed for oral administration: • Bioavailability in magnitude is incomplete only when erlotinib suspension is administered to norm-nourished rats. • Absorption rate constant is 52% lower when erlotinib solution is administered in undernourished rats as compared to the administration in norm-nourished rats. These results yield an expected 20% higher area under the concentration-time curve for erlotinib in undernourished patients as compared with norm-nourished ones. 7. Volume of distribution and bioavailability parameters for gefitinib are increased 30 and 50%, respectively, in protein-energy undernourishment status. This preclinical results yield simulation outcomes, which indicate that minimum trough concentration and area under the concentration-time curve in undernourished patients are expected to be 50% higher when compared to norm-nourished patients. 8. The response of the organism to compensate the deficiencies generated by an inadequate energy and protein intake is very complex. Consequently, general pharmacokinetic changes in undernourishment status are very variable, difficult to predict and dependent on the evaluated drug, given that all LADME processes are sensitive to these alterations.