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

Abstract

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 < .05), indicating that P-gp–dependent intestinal secretion is greater during the nighttime activity span than daytime rest span of the animals. P-gp modulators vinblastine and PSC833 led to a significant decrease of talinolol and losartan exsorption in the intestinal segments as compared with control groups. Strikingly, the permeability-enhancing effect of vinblastine and PSC833 was higher with night perfusions, for both talinolol and losartan. In vivo studies performed with talinolol revealed—consistent with the in situ studies (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 < .05), whereas only a weak vinblastine effect was seen in night. According to the in situ data, the functional activity of P-gp was regulated by the CTS in jejunum and ileum, which are major intestinal segments for energy-dependent efflux. In conclusion, circadian rhythms may affect carrier-mediated active efflux and play a role in the absorption process. In addition to daily rhythms in P-gp activity in rat intestine, the in vivo studies indicate that absorption-, distribution-, metabolism-, and elimination-relevant rhythms may be involved in the circadian kinetics of the drug, besides transporter-dependent efflux, such well-known aspects as metabolic or renal clearance or motility. Since this also holds true for a potentially interacting second compound (modulator), modulator effects should be evaluated carefully in transporter related drug-drug interactions. (Author correspondence: [email protected])

Keywords:

• Chronopharmacokinetics
• Circadian rhythm
• Intestinal perfusion
• Losartan
• P-glycoprotein
• Talinolol

ACKNOWLEDGMENTS

This work was supported by DAAD (German Academic Exchange Service; Bonn Germany) and the Research Fund of Istanbul University (YADOP-7401) to A.O., as well as a grant for scholarly training from the Government of Egypt to A.H. (None of these sources were involved in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication). A.O. received a travel grant for Graz University (KFU) from the Research Fund of Istanbul University (YADOP-7401). The support from SimulationsPlus to H.S.-L. is highly appreciated, the support from Pharsight is also acknowledged. The authors would like to thank Dr. Elisabeth Filipski and Dr. Zeliha Pala-Kara for their valuable comments.

Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.