Circadian Variations in Exsorptive Transport: In Situ Intestinal Perfusion Data and In Vivo Relevance

The circadian timing system (CTS) governs the 24-h rhythm of the organism and, hence, also main pathways responsible for drug pharmacokinetics. P-glycoprotein (P-gp) is a drug transporter that plays a pivotal role in drug absorption, distribution, and elimination, and temporal changes in its activity may affect input, output, activity, and toxicity profile of drugs. In the current study, the influence of different circadian stages on the overall intestinal permeability (P_eff) of the P-gp substrates talinolol and losartan was evaluated in in situ intestinal perfusion studies in rats. Additionally, in vivo studies in rats were performed by employing the P-gp probe talinolol during the day (nonactive) and night (active) period in rats. Effective intestinal permeabilities of talinolol and losartan were smaller in studies performed during the night (p?P_eff day?>?night)—a day vs. night difference in the oral availability of talinolol in the group of male rats in terms of the area under the curve (AUC) data (AUC_day?>?AUC_night). The P-gp modulator vinblastine significantly increased talinolol AUC_day (p?aokyar@istanbul.edu.tr)