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.

Diurnal Variation in P-glycoprotein-Mediated Transport and Cerebrospinal Fluid Turnover in the Brain

“…This is in line with several in vitro and in vivo studies that have shown 24-h variation in the expression and activity of P-gp in several different cell types (10–15). For example, Okyar et al (2012) found that the activity of P-gp in the intestine is higher during the active period of rats (13). Future studies investigating the activity of P-gp in different cell types of the CNS across the 24-h cycle may provide further information on the molecular mechanisms underlying the findings presented in this study.…”

P-glycoprotein Function in the Rodent Brain Displays a Daily Rhythm, a Quantitative In Vivo PET Study

“…So, all the studies in mice reported the peak of P-gp mRNA and protein expression in the intestine to be in the late sleep phase and in the liver in the early or mid-active phase. In contrast in rats, intestinal secretion of the P-gp substrates talinolol and losartan was greater during nocturnal activity (ZT13-ZT15) than daytime rest (ZT1-ZT3) (30). P-gp rhythm has been investigated also in daytimeactive cynomolgus monkeys (31).…”

Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine

“…Metabolism and elimination are altered by biological rhythms due to changes in perfusion, glomerular filtration rate, urine excretion rate, urine pH, and electrolyte balances [131,147,148]. Furthermore, circadian rhythms may modulate carrier-mediated transport activity significantly, leading to differences in absorption, intestinal metabolism, or even renal clearance [149,150,133]. Bioavailability of drugs that are P-glycoprotein substrates may have a dependence on circadian rhythms.…”