ABSTRACT
Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5®. Genetic polymorphism in CYP3A4, CYP3A5, CYP1A1, CYP2C9, and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of Cmax and AUC and increment of Vd in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite.
ABSTRACT
The physical and psychological fragility of patients with psychiatric illness poses critical importance in the preoperative assessment, evaluation, and choice of premedication, which includes regular therapy, as well as concerns about polypharmacy with possible interactions of anesthetics, analgesics, and psychiatric medications. A considerable effort is to reduce risks for exacerbations or relapses of imminent illness in the postoperative period. In this narrative review, the goal was also set towards the use of proper tools for the preoperative assessment of anxiety and management of postoperative pain. Indeed anxiety can be a manifestation of primary comorbidity within the spectrum of a major psychiatric condition and affects dramatically the presentations of other symptoms as well evolution. Pain perception is changed in patients with psychiatric illness; therefore, the postoperative bundle of measures including assessment of pain using tools adjusted to the patient's cognitive state and regular nonopioid analgesics is important aiming to minimize opioid use. Ketamine, esketamine, xenon, nitrous oxide, dexmedetomidine, and propofol seem to have a novel role and benefit the management of certain types of psychiatric illness during the perioperative period. Psychiatrist involvement is necessary throughout the perioperative period, starting preoperatively and continuing after discharge. Clinical pharmacologists should be part of the team during the management of critically ill patients when polypharmacy can cause undesirable effects. Psychosocial wellbeing of surgical patients with psychiatric co-morbidity depends deeply on the collaboration of medical staff, family, and friends and international guidelines aim to establish standards, including but not limited to postoperative management.
