Objective. This dissertation aims to evaluate factors impacting drug disposition and clinical outcomes.

Methods. Pharmacokinetic studies were conducted for gemcitabine in urothelial cancer, paclitaxel in breast cancer and capecitabine in colorectal caner among patients stratified into young and elderly groups. Cocktail consisting of chlorzoxazone (CYP2E1), caffeine (CYP1A2), dapsone (CYP3A4), mephenytoin (CYP2C19) and debrisoquine (CYP2D6) were administrated to OLTx patients to evaluate enzyme activity relating to recipient's age and post-operative duration. To assess renal P-gp activity in cystic fibrosis (CF) patients, disposition of fexofenadine was evaluated and P-gp efflux activity in peripheral T cells was measured by flow cytometry. To assess interactions between tenofovir and ritonavir, renal function of HIV-infected patients were evaluated and tenofovir disposition was compared relating to regiments administrated. Kidney cell lines, MDCKII and HEK293, were treated with tenofovir alone or in combination with ritonavir or MK571 to assess the impact of ritonavir on intracellular tenofovir accumulation.

Results. Compared to patients less than 60, elderly patients (>70 years) had significantly greater AUCs and less clearance for paclitaxel and capecitabine and greater AUC of dFdU. The CYP2E1 activity was significantly elevated and CYP2C19 function was markedly reduced in OLTx patients, where CYP2D6 capacity was impaired in older OLTx patients within 30 days postoperatively compared to healthy controls. The P-gp efflux activity in peripheral T cells was not significantly different between CF and HV. Fexofenadine pharmacokinetics was similar in CF and HV when administered alone or with probenecid. ABCB1 3435 C/T carriers showed increased basal P-gp activity in peripheral T cells and decreased fexofenadine AUC. Patients receiving concurrent TDF+PI/r treatment had greater reductions in CrCl and lower TFV Kel compared to patients taking TDF+NNRTI. TFV was substrate of MRP2, MRP4 and MRP5, where RTV was a potent inhibitor of MRP2 leading to nephrotoxicity with TDF-RTV coadministration.

Conclusion. Impaired renal elimination and hepatic metabolic capacity are major factors accounting for altered pharmacokinetics in elderly patients. Inhibition of transporters contributes to variations in drug disposition. Genetic polymorphisms in enzymes and transporters add to complexities of inter-individual differences in pharmacokinetics and clinical outcomes.