Selection of Healthy Volunteers According to their Multidrug Resistance Protein 1 Activity Does Not Affect Bioavailability of Quetiapine

Background: Quetiapine - an antipsychotic multidrug resistance protein 1 (MDR-1) substrate - has a large interindividual variability in its pharmacokinetics. Objective: In order to unravel the true effect of MDR-1 activity in the plasma levels of quetiapine, we studied the bioavailability of quetiapine in healthy subjects with different transporter activity. Method: Fifty-four Mexican mestizo healthy subjects, both male and female, with a median age of 32, were enrolled in a bioavailability study. Before starting the clinical trial, a flow cytometric daunorubicin-efflux assay was carried out in peripheral blood leukocytes to determine their MDR-1 phenotype. Plasma concentrations of quetiapine were monitored by an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC/MS/MS). The trial was approved by the Ethics Committee of our institution and by the Federal Commission for the Protection against Sanitary Risks (COFEPRIS) of Mexico. All subjects provided written informed consent before screening. Results: Subjects were classified as having high or low MDR-1 activity, according to the relative fluores- cence intensity of efflux of daunorubicin from their leukocytes. Although the maximum concentration (Cmax) of quetiapine in plasma was reached earlier in the high MDR-1 subjects, the overall pharmacokinetic profile was not different between both groups. Conclusion: MDR-1 activity in leukocytes does not affect significantly the bioavailability of a single dose of queti- apine in healthy individuals. Thus, interindividual differences in pharmacokinetics and subsequently clinical response to quetiapine cannot be predicted only by flow cytometric measurement of MDR-1 activity in leukocytes.