| Novel techniques in the study of pharmacokinetics (PK) are presented in two ways: firstly, through the theoretical approach and secondly, through the experimental approach. The theoretical approach involves developing new Pharmacokinetic-Metabolism (PK-MB) models that would be used to optimize patient care with such drugs as ifosfamide and ciprofloxacin. Then, a new method for phenotyping individuals for their drug metabolizing activity as it is related to specific cytochrome P450 enzymes (CYP3A4, CYP2D6) and P-glycoprotein is presented. The second way to evaluate and improve PK studies is through the experimental approach to pharmacokinetics which involves developing new, faster and efficient ways to analyze the data needed for reliable PK-MB models.; Firstly, a one compartmental PK-MB model was developed to evaluate the plasma and urine concentrations of ifosfamide and 4 of its metabolites in a simultaneous manner for cancer patients. Secondly, ciprofloxacin (a fluoroquinolone antibiotic) was studied as a prophylaxis treatment of endophthalmitis in 26 patients before they underwent vitrectomy. All patients were phenotyped for their CYP1A2 activity, the enzyme metabolizing ciprofloxacin, with caffeine. A population PK-MB model integrating CYP1A2 activity, was developed to describe ciprofloxacin concentrations in plasma, vitreous and aqueous humor simultaneously. The third research project was the development of a new method to phenotype subjects for their CYP3A4, CYP2D6 and P-glycoprotein activities using dextromethorphan ([DM]: cough medicine) as the probe drug.; In conclusion, the research in 2 studies presents a unique population PK-MB compartmental modeling technique incorporating the successful integration of the knowledge from two disciplines: metabolism and PK. For instance, the study employing a PK-MB model in cancer patients receiving (R,S)-Ifosfamide demonstrates that this approach can accommodate stereoselective metabolism, auto-induction, and individual drug metabolism capabilities. The model predicts individual patient's toxic or therapeutic response based on PK-MB parameters and therefore can be a valuable guide in ifosfamide therapy. PK studies requires experimental data that needs to be obtained in an ever more faster and efficient manner. Hence, the next set of experiments in this thesis aims at studying the interactions between enzyme and substrate in a more efficient and reproducible manner through immobilized enzyme reactors. (Abstract shortened by UMI.)... |
